Thomas Sæther

Galigniana NM, Abdelhalim M, Collas P, Sæther T (2024). Transcriptional and metabolic changes following repeated fasting and refeeding of adipose stem cells highlight adipose tissue resilience. Nutrients, 16(24):4310.

Nolsøe JMJ, Underhaug J, Sørskar ÅM, Antonsen SG, Malterud KE, Gani O, Fan Q, Hjorth M, Sæther T, Hansen TV, Stenstrøm YH (2024). Biological Evaluations, NMR Analyses, Molecular Modelling Studies, and Overview of the Synthesis of the Marine Natural Product (-)-Mucosin. Molecules, 29(5):994.

Canet F, Christensen JJ, Victor VM, Hustad KS, Ottestad I, Rundblad A, Sæther T, Dalen KT, Ulven SM, Holven KB, Telle-Hansen VH (2022). Glycated proteins, glycine, acetate, and monounsaturated fatty acids may act as new biomarkers to predict progression of type 2 diabetes: secondary analyses of a randomized controlled trial. Nutrients, 14(23):5165.

Hjorth M, Doncheva A, Norheim F, Ulven SM, Holven KB, Sæther T, Dalen KT (2022). Consumption of salmon fishmeal increases hepatic cholesterol content in obese C57BL/6J mice. Eur J Nutr, 61(8):4027-4043.

Hjorth M, Galigniana NM, Ween O, Ulven SM, Holven KB, Dalen KT, Sæther T (2022). Postprandial Effects of Salmon Fishmeal and Whey on Metabolic Markers in Serum and Gene Expression in Liver Cells. Nutrients, 14(8):1593.

Hustad KS, Ottestad I, Olsen T, Sæther T, Ulven SM, Holven KB (2022). Salmon fish protein supplement increases serum vitamin B12 and selenium concentrations: secondary analysis of a randomized controlled trial. Eur J Nutr, 61(6):3085-3093.

Stabell M, Sæther T, Røhr AK, Gabrielsen OS, Myklebost O (2021). Methylation-dependent SUMOylation of the architectural transcription factor HMGA2. Biochem Biophys Res Commun, 552:91-97.

Hustad KS, Ottestad I, Hjorth M, Dalen KT, Sæther T, Sheikh NA, Strømnes M, Ulven SM, Holven KB (2021). No effect of salmon fishmeal on 2h-glucose in adults with increased risk of 2 type 2 diabetes: a randomised controlled trial. Br J Nutr, 126:1304-13.

Fan Q, Nørgaard RC, Grytten I, Ness CM, Lucas C, Vekterud K, Soedling H, Matthews J, Lemma RB, Gabrielsen OS, Bindesbøll C, Ulven SM, Nebb HI, Grønning-Wang LM, Sæther T (2020). LXRα Regulates ChREBPα Transactivity in a Target Gene-Specific Manner through an Agonist-Modulated LBD-LID Interaction. Cells, 9(5):1214.

Brunet A, Forsberg F, Fan Q, Sæther T, Collas P (2019). Nuclear Lamin B1 Interactions with Chromatin during the Circadian Cycle Are Uncoupled from Periodic Gene Expression. Front Genet 10:917.

Arnesen H, Haj-Yasein NN, Tungen JE, Soedling H, Matthews J, Paulsen SM, Nebb HI, Sylte I, Hansen TV, Sæther T (2019). Molecular modelling, synthesis, and biological evaluations of a 3,5-disubstituted isoxazole fatty acid analogue as a PPARα-selective agonist. Bioorg Med Chem 27(18):4059-68.

Sæther T, Paulsen SM, Tungen JE, Vik A, Aursnes M, Holen T, Hansen TV, Nebb HI (2018). Synthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effects. Eur J Med Chem 155:736-753.

Fan Q, Moen A, Anonsen JH, Bindesbøll C, Sæther T, Carlson CR, Grønning-Wang LM (2018) O-GlcNAc site-mapping of liver X receptor-α and O-GlcNAc transferase. Biochem Biophys Res Commun 499(2):354-360.

Moldes-Anaya, A, Sæther T, Uhlig S, Nebb HI, Larsen T, Eilertsen HC, Paulsen SM (2017). Two Isomeric C16 Oxo-Fatty Acids from the Diatom Chaetoceros karianus Show Dual Agonist Activity towards Human Peroxisome Proliferator-Activated Receptors (PPARs) α/γ. Mar Drugs 15(6):148.

Lorenzo PI, Brendeford EM, Gilfillan S, Gavrilov AA, Leedsak M, Razin SV, Eskeland R, Sæther T, Gabrielsen OS (2011) Identification of c-Myb target genes in K562 cells reveals a role for c-Myb as a master regulator. Genes Cancer 2(8):805-17.

Haugen TB, Tefre T, Malm G, Jönsson BA, Rylander L, Hagmar L, Bjørsvik C, Henrichsen T, Sæther T, Figenschau Y, Giwercman A (2011) Differences in serum levels of CB-153 and p,p'-DDE, and reproductive parameters between men living south and north in Norway. Reprod Toxicol 32(3):261-7.

Alm-Kristiansen AH, Lorenzo PI, Molværsmyr AK, Matre V, Ledsaak M, Sæther T, Gabrielsen OS (2011) PIAS1 interacts with FLASH and enhances its co-activation of c-Myb. Mol Cancer 10:21.

Sæther T, Pattabiraman DR, Alm-Kristiansen AH, Vogt-Kielland LT, Gonda TJ, Gabrielsen OS (2011) A functional SUMO-interacting motif in the transactivation domain of c-Myb regulates its myeloid transforming ability. Oncogene 30(2):212-22.

Molværsmyr AK, Sæther T, Gilfillan S, Lorenzo PI, Kvaløy H, Matre V, Gabrielsen OS (2010) A SUMO-regulated activation function controls synergy of c-Myb through a repressor-activator switch leading to differential p300 recruitment. Nucleic Acids Res 38(15):4970-84.

Rylander L, Wetterstrand B, Haugen TB, Malm G, Malm J, Bjørsvik C, Henrichsen T, Sæther T, Giwercman A (2009) Single semen analysis as a predictor of semen quality: clinical and epidemiological implications. Asian J Androl 11(6):723-30.

Alm-Kristiansen AH, Sæther T, Matre V, Gilfillan S, Dahle O, Gabrielsen OS (2008). FLASH acts as a co-activator of the transcription factor c-Myb and localizes to active RNA polymerase II foci. Oncogene 27(34):4644-56.

Berge T, Matre V, Brendeford EM, Sæther T, Lüscher B, Gabrielsen OS (2007) Revisiting a selection of target genes for the hematopoietic transcription factor c-Myb using chromatin immunoprecipitation and c-Myb knockdown. Blood Cells Mol Dis 39(3):278-86.

Ruhayel Y, Malm G, Haugen TB, Henrichsen T, Bjørsvik C, Grotmol T, Sæther T, Malm J, Figenschau Y, Rylander L, Levine RJ, Giwercman A (2007) Seasonal variation in serum concentrations of reproductive hormones and urinary excretion of 6-sulfatoxymelatonin in men living north and south of the Arctic Circle: a longitudinal study. Clin Endocrinol (Oxf). 67(1):85-92.

Sæther T, Berge T, Ledsaak M, Matre V, Alm-Kristiansen AH, Dahle O, Aubry F, Gabrielsen OS (2007) The chromatin remodeling factor Mi-2alpha acts as a novel co-activator for human c-Myb. J Biol Chem 282(19):13994-4005.

Sæther T, Tran TN, Rootwelt H, Grav HJ, Christophersen BO, Haugen TB (2007) Essential fatty acid deficiency induces fatty acid desaturase expression in rat epididymis, but not in testis. Reproduction 133(2):467-77.

Aschim EL, Sæther T, Wiger R, Grotmol T, Haugen TB (2004). Differential distribution of splice variants of estrogen receptor beta in human testicular cells suggests specific functions in spermatogenesis. J Steroid Biochem Mol Biol 92(1-2):97-106.

Malm G, Haugen TB, Henrichsen T, Bjørsvik C, Grotmol T, Sæther T, Malm J, Figenschau Y, Hagmar L, Rylander L, Levine RJ, Giwercman A (2004) Reproductive function during summer and winter in Norwegian men living north and south of the Arctic circle. J Clin Endocrinol Metab 89(9):4397-402.

Sæther T, Tran TN, Rootwelt H, Christophersen BO, Haugen TB (2003) Expression and regulation of delta5-desaturase, delta6-desaturase, stearoyl-coenzyme A (CoA) desaturase 1, and stearoyl-CoA desaturase 2 in rat testis. Biol Reprod 69(1):117-24.

• Sæther, Thomas; Starholm, Trude Irene Thunshelle & Hobøl, Erling (2024). Negative population trend of the Reed Bunting Emberiza schoeniclus in an important wetland in southeastern Norway. Ornis Norvegica. 47, p. 13–24. doi: 10.15845/on.v47.3953. Full text in Research Archive Show summary

  The Reed Bunting Emberiza schoeniclus is considered the most common of the five species of Emberiza buntings breeding in Norway and is currently listed as a species of Least Concern. However, a complete census of territorial male Reed Buntings conducted in the Nordre Øyeren nature reserve in 2019 showed a decline in the local breeding population of 67% compared to the last counts completed 40 years ago. Censuses were conducted in 1976 and 1981 in the same area and with the same methods. Analyses of citizen science data from the Norwegian Biodiversity Information Centre also show a similar decreasing trend (-66%) for the Reed Bunting breeding population in Nordre Øyeren from 1976 to 2019. Moreover, image analyses of the census maps show that that the number and density of Reed Bunting territories have decreased locally and probably has done so since early 1980s. Interestingly, a subset of localities within the survey area still have the same territory densities as the 1976 and 1981 censuses. We suggest that changes in habitat, vegetation and farming practice, especially grazing, could be the underlying cause of variation in bird numbers. Our results indicate a negative population trend for the Reed Bunting locally, a tendency that is also observed regionally in the Nordic countries. Taken together, local and regional declines raise concerns about the conservation status of the Reed Bunting in Norway.

• Nolsøe, Jens Mortansson Jelstrup; Underhaug, Jarl; Sørskår, Åshild Moi; Antonsen, Simen; Malterud, Karl Egil & Gani, Osman [Show all 11 contributors for this article] (2024). Biological Evaluations, NMR Analyses, Molecular Modeling Studies, and Overview of the Synthesis of the Marine Natural Product (−)-Mucosin. Molecules. ISSN 1431-5157. 29(5). doi: 10.3390/molecules29050994. Full text in Research Archive Show summary

  Natural products obtained from marine organisms continue to be a rich source of novel structural architecture and of importance in drug discovery, medicine, and health. However, the success of such endeavors depends on the exact structural elucidation and access to sufficient material, often by stereoselective total synthesis, of the isolated natural product of interest. (−)-Mucosin (1), a fatty acid derivative, previously presumed to contain a rare cis-bicyclo[4.3.0]non-3-ene moiety, has since been shown to be the trans-congener. Analytically, the fused bicyclic ring system in (−)-1 constitutes a particular challenge in order to establish its relative and absolute stereochemistry. Herein, data from biological evaluations, NMR and molecular modeling studies of (−)-1 are presented. An overview of the synthetic strategies enabling the exact structural elucidation of (−)-mucosin (1) is also presented.

• Galigniana, Natalia Maricel; Abdelhalim, Mohamed Ibrahim Mohamed; Collas, Philippe & Sæther, Thomas (2024). Transcriptional and Metabolic Changes Following Repeated Fasting and Refeeding of Adipose Stem Cells Highlight Adipose Tissue Resilience. Nutrients. 16(24). doi: 10.3390/nu16244310. Full text in Research Archive Show summary

  Background: Obesity and related metabolic disorders have reached epidemic levels, calling for diverse therapeutic strategies. Altering nutrient intake, timing and quantity by intermittent fasting seems to elicit beneficial health effects by modulating endocrine and cell signaling networks. This study explores the impact of cyclic nutrient availability in the form of every-other-day fasting (EODF) on human adipose stem cells (ASCs). Methods: We subjected ASCs to repeated fasting/refeeding (F/R) cycles, mimicking low glucose/high fatty acid (LGHF) conditions, and assessed phenotypic and transcriptomic changes, lipid storage capacity, insulin sensitivity, and differentiation potential. Results: Four consecutive F/R cycles induced significant changes in adipogenic gene expression, with upregulation of FABP4 and PLIN1 during fasting, and increased lipid storage in the ASCs. Upon differentiation, ASCs exposed to LGHF conditions retained a transient increase in lipid droplet size and altered fatty acid metabolism gene expression until day 9. However, these changes dissipated by day 15 of differentiation, suggesting a limited duration of fasting-induced transcriptional and adipogenic memory. Despite initial effects, ASCs showed resilience, returning to a physiological trajectory during differentiation, with respect to gene expression and lipid metabolism. Conclusions: These findings suggest that the long-term effects of EODF on the ASC niche may be transient, emphasizing the ability of the adipose tissue to adapt and restore homeostasis.

• Hustad, Kristin Solheim; Ottestad, Inger; Olsen, Thomas; Sæther, Thomas; Ulven, Stine Marie & Holven, Kirsten Bjørklund (2022). Salmon fish protein supplement increases serum vitamin B12 and selenium concentrations: secondary analysis of a randomised controlled trial. European Journal of Nutrition. ISSN 1436-6207. 61(6), p. 3085–3093. doi: 10.1007/s00394-022-02857-4. Full text in Research Archive Show summary

  Abstract Purpose The main aim of the present study was to examine the effect of a fish protein supplement made from by-products from production of Atlantic salmon, on blood concentration of micronutrients. Methods We conducted an 8-week double-blind parallel-group randomised controlled trial. In total, 88 adults were randomised to a salmon fish protein supplement or placebo, and 74 participants were included in the analysis of vitamin D, omega-3, vitamin B12, selenium, folate, zinc, homocysteine and mercury. Results During the intervention period, geometric mean (GSD) of serum vitamin B12 concentrations increased from 304 (1.40) to 359 (1.42) pmol/L in the fish protein group ( P vs. controls = 0.004) and mean (SD) serum selenium increased from 1.18 (0.22) to 1.30 (0.20) μmol/L ( P vs. controls = 0.002). The prevalence of low vitamin B12 status (B12 < 148–221 > pmol/L) decreased from 15.4 to 2.6% in the fish protein group, while increasing from 5.9 to 17.6% in the placebo group ( P  = 0.045). There was no difference between the groups in serum levels of the other micronutrients measured. Conclusion Including a salmon fish protein supplement in the daily diet for 8 weeks, increases serum vitamin B12 and selenium concentrations. From a sustainability perspective, by-products with high contents of micronutrients and low contents of contaminants, could be a valuable dietary supplement or food ingredient in populations with suboptimal intake. Trail Registration The study was registered at ClinicalTrials.gov (ID: NCT03764423) on June 29th 2018.

• Hjorth, Marit; Galigniana, Natalia; Ween, Ola; Ulven, Stine Marie; Holven, Kirsten Bjørklund & Dalen, Knut Tomas [Show all 7 contributors for this article] (2022). Postprandial Effects of Salmon Fishmeal and Whey on Metabolic Markers in Serum and Gene Expression in Liver Cells. Nutrients. 14(8). doi: 10.3390/nu14081593. Full text in Research Archive Show summary

  Fish is considered an important part of a healthy diet, in part due to the content of long chain omega-3 fatty acids. However, both lean and fatty fish have beneficial health effects, suggesting that micronutrients and proteins may play a role. In a randomised, controlled, cross-over trial, five healthy male participants consumed 5.2 g of protein from either salmon fishmeal or whey. Blood samples were taken before and 30 and 60 min after intake. The concentration of glucose, lipids, hormones and metabolites, including 28 different amino acids and derivatives, were measured in serum or plasma. Cultured HepG2 cells were incubated with or without serum from the participants, and transcriptomic profiling was performed using RNA sequencing. The ingestion of both salmon fishmeal and whey reduced the glucose and triglyceride levels in serum. Protein intake, independent of the source, increased the concentration of 22 amino acids and derivatives in serum. Fishmeal increased the concentration of arginine, methionine, serine, glycine, cystathionine and 2-aminobutyric acid more than whey did. Incubation with postprandial serum resulted in large transcriptomic alterations in serum-fasted HepG2 cells, with the differential expression of >4500 protein coding genes. However, when comparing cells cultivated in fasting serum to postprandial serum after the ingestion of fishmeal and whey, we did not detect any differentially regulated genes, neither with respect to the protein source nor with respect to the time after the meal. The comparable nutrigenomic effects of fishmeal and whey do not change the relevance of fish by-products as an alternative food source.

• Canet, Francisco; Christensen, Jacob J.; Victor, Victor M.; Hustad, Kristin Solheim; Ottestad, Inger & Rundblad, Amanda [Show all 11 contributors for this article] (2022). Glycated proteins, glycine, acetate, and monounsaturated fatty acids may act as new biomarkers to predict the progression of type 2 diabetes: Secondary analyses of a randomized controlled trial. Nutrients. 14(23), p. 1–19. doi: 10.3390/nu14235165. Full text in Research Archive Show summary

  Food protein or food-derived peptides may regulate blood glucose levels; however, studies have shown inconsistent results. The aim of the present study was to characterize subgroups of individuals with increased risk of type 2 diabetes (T2D) and to investigate the cardiometabolic effects of fish protein in the same subgroups. We first divided participants into high insuliniAUC and low insuliniAUC subjects based on their insulin incremental area under the curve (iAUC) levels after a 2 h oral glucose tolerance test (OGTT), and secondly based on whether they had received 5.2 g salmon fish protein or placebo for 8 weeks, in a previously conducted randomized controlled trial (RCT). We then profiled these groups by analyzing plasma metabolomics and peripheral blood mononuclear cell (PBMC) gene expression. Compared to the low insuliniAUC group, the high insuliniAUC group had higher plasma concentrations of monounsaturated fatty acids (MUFAs) and glycated proteins (GlycA) and lower concentrations of glycine and acetate. After intervention with fish protein compared to placebo, however, only acetate was significantly increased in the low insuliniAUC group. In conclusion, we identified metabolic biomarkers known to be associated with T2D; also, intervention with fish protein did not affect cardiometabolic risk markers in subgroups with increased risk of T2D.

• Hjorth, Marit; Doncheva, Atanaska Ivanova; Norheim, Frode Amador; Ulven, Stine Marie; Holven, Kirsten Bjørklund & Sæther, Thomas [Show all 7 contributors for this article] (2022). Consumption of salmon fishmeal increases hepatic cholesterol content in obese C57BL/6 J mice. European Journal of Nutrition. ISSN 1436-6207. 61, p. 4027–4043. doi: 10.1007/s00394-022-02930-y. Full text in Research Archive Show summary

  Abstract Purpose By-products from farmed fish contain large amounts of proteins and may be used for human consumption. The purpose of this study was to investigate cardiometabolic effects and metabolic tolerance in mice consuming fishmeal from salmon by-products, salmon filet or beef. Methods Female C57BL/6J mice were fed chow, as a healthy reference group, or a high-fat diet for 10 weeks to induce obesity and glucose intolerance. Obese mice were subsequently given isocaloric diets containing 50% of the dietary protein from salmon fishmeal, salmon filet or beef for 10 weeks. Mice were subjected to metabolic phenotyping, which included measurements of body composition, energy metabolism in metabolic cages and glucose tolerance. Lipid content and markers of hepatic toxicity were determined in plasma and liver. Hepatic gene and protein expression was determined with RNA sequencing and immunoblotting. Results Mice fed fishmeal, salmon filet or beef had similar food intake, energy consumption, body weight gain, adiposity, glucose tolerance and circulating levels of lipids and hepatic toxicity markers, such as p-ALT and p-AST. Fishmeal increased hepatic cholesterol levels by 35–36% as compared to salmon filet (p = 0.0001) and beef (p = 0.005). This was accompanied by repressed expression of genes involved in steroid and cholesterol metabolism and reduced levels of circulating Pcsk9. Conclusion Salmon fishmeal was well tolerated, but increased hepatic cholesterol content. The high cholesterol content in fishmeal may be responsible for the effects on hepatic cholesterol metabolism. Before introducing fishmeal from salmon by-products as a dietary component, it may be advantageous to reduce the cholesterol content in fishmeal. Introduction

• Hustad, Kristin Solheim; Ottestad, Inger Olaug; Hjorth, Marit; Dalen, Knut Tomas; Sæther, Thomas & Sheikh, Navida Akhter [Show all 9 contributors for this article] (2021). No effect of salmon fish protein on 2-h glucose in adults with increased risk of type 2 diabetes: a randomised controlled trial. British Journal of Nutrition. ISSN 0007-1145. 126(9), p. 1304–1313. doi: 10.1017/S0007114521000040. Full text in Research Archive Show summary

  Abstract The association between fish consumption and decreased risk of CVD is well documented. However, studies on health effects of fish consumption suggest that other components than n -3 PUFA have beneficial cardiometabolic effects, including effects on glucose metabolism. The aim of the present study was to investigate effects of salmon fish protein on cardiometabolic risk markers in a double-blind, randomised controlled parallel trial. We hypothesised that daily intake of a salmon fish protein supplement for 8 weeks would improve glucose tolerance in persons with increased risk of type 2 diabetes mellitus (T2DM). Our primary outcome measure was serum glucose (s-glucose) 2 h after a standardised oral glucose tolerance test. In total, eighty-eight adults with elevated s-glucose levels were randomised to 7·5 g of salmon fish protein/d or placebo, and seventy-four participants were included in the analysis. We found no significant effect of salmon fish protein supplementation on our primary outcome or other markers related to glucose tolerance, serum lipids, weight or blood pressure compared with placebo. The present study does not support the hypothesis that daily intake of a salmon fish protein supplement for 8 weeks improves glucose tolerance in persons with increased risk of T2DM.

• Stabell, Marianne; Sæther, Thomas; Kjendseth, Åsmund Røhr; Gabrielsen, Odd Stokke & Myklebost, Ola (2021). Methylation-dependent SUMOylation of the architectural transcription factor HMGA2. Biochemical and Biophysical Research Communications - BBRC. ISSN 0006-291X. 552, p. 91–97. doi: 10.1016/j.bbrc.2021.02.099. Full text in Research Archive Show summary

  High mobility group A2 (HMGA2) is a chromatin-associated protein involved in the regulation of stem cell function, embryogenesis and cancer development. Although the protein does not contain a consensus SUMOylation site, it is shown to be SUMOylated. In this study, we demonstrate that the first lysine residue in the reported K66KAE SUMOylation motif in HMGA2 can be methylated in vitro and in vivo by the Set7/9 methyltransferase. By editing the lysine, the increased hydrophobicity of the resulting 6-N-methyl-lysine transforms the sequence into a consensus SUMO motif. This post-translational editing dramatically increases the subsequent SUMOylation of this site. Furthermore, similar putative methylation-dependent SUMO motifs are found in a number of other chromatin factors, and we confirm methylation-dependent SUMOylation of a site in one such protein, the Polyhomeotic complex 1 homolog (PHC1). Together, these results suggest that crosstalk between methylation and SUMOylation is a general mode for regulation of chromatin function.

• Fan, Qiong; Nørgaard, Rikke Christine; Grytten, Ivar; Ness, Cecilie; Lucas, Christin & Vekterud, Kristin [Show all 15 contributors for this article] (2020). LXRα Regulates ChREBPα Transactivity in a Target Gene-Specific Manner through an Agonist-Modulated LBD-LID Interaction. Cells. 9(5), p. 1–26. doi: 10.3390/cells9051214. Full text in Research Archive Show summary

  The cholesterol-sensing nuclear receptor liver X receptor (LXR) and the glucose-sensing transcription factor carbohydrate responsive element-binding protein (ChREBP) are central players in regulating glucose and lipid metabolism in the liver. More knowledge of their mechanistic interplay is needed to understand their role in pathological conditions like fatty liver disease and insulin resistance. In the current study, LXR and ChREBP co-occupancy was examined by analyzing ChIP-seq datasets from mice livers. LXR and ChREBP interaction was determined by Co-immunoprecipitation (CoIP) and their transactivity was assessed by real-time quantitative polymerase chain reaction (qPCR) of target genes and gene reporter assays. Chromatin binding capacity was determined by ChIP-qPCR assays. Our data show that LXRα and ChREBPα interact physically and show a high co-occupancy at regulatory regions in the mouse genome. LXRα co-activates ChREBPα and regulates ChREBP-specific target genes in vitro and in vivo. This co-activation is dependent on functional recognition elements for ChREBP but not for LXR, indicating that ChREBPα recruits LXRα to chromatin in trans. The two factors interact via their key activation domains; the low glucose inhibitory domain (LID) of ChREBPα and the ligand-binding domain (LBD) of LXRα. While unliganded LXRα co-activates ChREBPα, ligand-bound LXRα surprisingly represses ChREBPα activity on ChREBP-specific target genes. Mechanistically, this is due to a destabilized LXRα:ChREBPα interaction, leading to reduced ChREBP-binding to chromatin and restricted activation of glycolytic and lipogenic target genes. This ligand-driven molecular switch highlights an unappreciated role of LXRα in responding to nutritional cues that was overlooked due to LXR lipogenesis-promoting function.

• Brunet, Annaëlle; Forsberg, Anna Frida; Fan, Qiong; Sæther, Thomas & Collas, Philippe (2019). Nuclear lamin B1 interactions with chromatin during the circadian cycle are uncoupled from periodic gene expression. Frontiers in Genetics. 10. doi: 10.3389/fgene.2019.00917. Full text in Research Archive Show summary

  Many mammalian genes exhibit circadian expression patterns concordant with periodic binding of transcription factors, chromatin modifications, and chromosomal interactions. Here we investigate whether chromatin periodically associates with nuclear lamins. Entrainment of the circadian clock is accompanied, in mouse liver, by a net gain of lamin B1–chromatin interactions genome-wide, after which the majority of lamina-associated domains (LADs) are conserved during the circadian cycle. By tailoring a bioinformatics pipeline designed to identify periodic gene expression patterns, we also observe hundreds of variable lamin B1-chromatin interactions among which oscillations occur at 64 LADs, affecting one or both LAD extremities or entire LADs. Only a small subset of these oscillations however exhibit highly significant 12, 18, 24, or 30 h periodicity. These periodic LADs display oscillation asynchrony between their 5′ and 3′ borders, and are uncoupled from periodic gene expression within or in the vicinity of these LADs. Periodic gene expression is also unrelated to variations in gene-to-nearest LAD distances detected during the circadian cycle. Accordingly, periodic genes, including central clock-control genes, are located megabases away from LADs throughout circadian time, suggesting stable residence in a transcriptionally permissive chromatin environment. We conclude that periodic LADs are not a dominant feature of variable lamin B1–chromatin interactions during the circadian cycle in mouse liver. Our results also suggest that periodic hepatic gene expression is not regulated by rhythmic chromatin associations with the nuclear lamina.

• Arnesen, Liv Henriette; Yasein, Nadia Haj; Tungen, Jørn Eivind; Södling, Helen; Matthews, Jason & Paulsen, Steinar M [Show all 10 contributors for this article] (2019). Molecular modelling, synthesis, and biological evaluations of a 3,5-disubstituted isoxazole fatty acid analogue as a PPARα-selective agonist. Bioorganic & Medicinal Chemistry. ISSN 0968-0896. 27(18), p. 4059–4068. doi: 10.1016/j.bmc.2019.07.032. Full text in Research Archive Show summary

  The peroxisome proliferator activated receptors (PPARs) are important drug targets in treatment of metabolic and inflammatory disorders. Fibrates, acting as PPARα agonists, have been widely used lipid-lowering agents for decades. However, the currently available PPARα targeting agents show low subtype-specificity and consequently a search for more potent agonists have emerged. In this study, previously isolated oxohexadecenoic acids from the marine algae Chaetoceros karianus were used to design a PPARα-specific analogue. Herein we report the design, synthesis, molecular modelling studies and biological evaluations of the novel 3,5-disubstituted isoxazole analogue 6-(5-heptyl-1,2-oxazol-3-yl)hexanoic acid (1), named ADAM. ADAM shows a clear receptor preference and significant dose-dependent activation of PPARα (EC50 = 47 µM) through its ligand-binding domain (LBD). Moreover, ADAM induces expression of important PPARα target genes, such as CPT1A, in the Huh7 cell line and primary mouse hepatocytes. In addition, ADAM exhibits a moderate ability to regulate PPARγ target genes and drive adipogenesis. Molecular modelling studies indicated that ADAM docks its carboxyl group into opposite ends of the PPARα and -γ LBD. ADAM interacts with the receptor-activating polar network of amino acids (Tyr501, His447 and Ser317) in PPARα, but not in PPARγ LBD. This may explain the lack of PPARγ agonism, and argues for a PPARα-dependent adipogenic function. Such compounds are of interest towards developing new lipid-lowering remedies.

• Fan, Qiong; Nørgaard, Rikke Christine; Grytten, Ivar; Ness, Cecilie Maria; Lucas, Christin & Vekterud, Kristin [Show all 15 contributors for this article] (2019). Open the LID: LXRα regulates ChREBPα transactivity in a target gene-specific manner through an agonist-modulated LBD-LID interaction. BioRxiv. ISSN 0362-4331. doi: 10.1101/2019.12.20.869974. Full text in Research Archive Show summary

  The cholesterol-sensing nuclear receptor liver X receptor (LXR) and the glucose-sensing transcription factor carbohydrate responsive element-binding protein (ChREBP) are central players in regulating glucose and lipid metabolism in liver. We have previously shown that LXR regulates ChREBP transcription and activity; however, the underlying mechanisms are unclear. In the current study, we demonstrate that LXRα and ChREBPα interact physically, and show a high co-occupancy at regulatory regions in the mouse genome. LXRα co-activates ChREBPα, and regulates ChREBP-specific target genes in vitro and in vivo. This co-activation is dependent on functional recognition elements for ChREBP, but not for LXR, indicating that ChREBPα recruits LXRα to chromatin in trans. The two factors interact via their key activation domains; ChREBPα’s low glucose inhibitory domain (LID) and the ligand-binding domain (LBD) of LXRα. While unliganded LXRα co-activates ChREBPα, ligand-bound LXRα surprisingly represses ChREBPα activity on ChREBP-specific target genes. Mechanistically, this is due to a destabilized LXRα:ChREBPα interaction, leading to reduced ChREBP-binding to chromatin and restricted activation of glycolytic and lipogenic target genes. This ligand-driven molecular switch highlights an unappreciated role of LXRα that was overlooked due to LXR lipogenesis-promoting function.

• Sæther, Thomas; Paulsen, Steinar M; Tungen, Jørn Eivind; Vik, Anders; Aursnes, Marius & Holen, Torgeir [Show all 8 contributors for this article] (2018). Synthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effects. European Journal of Medicinal Chemistry. ISSN 0223-5234. 155, p. 736–753. doi: 10.1016/j.ejmech.2018.06.034. Full text in Research Archive Show summary

  Obesity and associated disorders such as metabolic syndrome and type 2 diabetes (T2D) have reached epidemic proportions. Several natural products have been reported as Peroxisome Proliferator-Activated Receptor (PPAR) agonists, functioning as lead compounds towards developing new anti-diabetic drugs due to adverse side effects of existing PPAR drugs. We recently isolated and identified (7E)-9-oxohexadec-7-enoic acid (1) and (10E)-9-oxohexadec-10-enoic acid (2) from the marine algae Chaetoceros karianus. Herein we report the total synthesis, pharmacological characterization, and biological evaluations of these naturally occurring oxo-fatty acids (oFAs). The syntheses of 1 and 2 afforded sufficient material for extensive biological evaluations. Both oFAs show an appreciable dose-dependent activation of PPARα and -γ, with EC50 values in the micromolar range, and an ability to regulate important PPAR target genes in hepatocytes and adipocytes. Moreover, both 1 and 2 are able to drive adipogenesis when evaluated in the Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocyte cell model, but with lowered expression of adipocyte markers and reduced lipid accumulation compared to the drug rosiglitazone. This seems to be caused by a transient upregulation of PPARγ and C/EBPα expression. Importantly, whole transcriptome analysis shows that both compounds induce anti-diabetic gene programs in adipocytes by upregulating insulin-sensitizing adipokines and repressing pro-inflammatory cytokines.

• Fan, Qiong; Moen, Anders; Anonsen, Jan Haug; Bindesbøll, Christian; Sæther, Thomas & Carlson, Cathrine Rein [Show all 7 contributors for this article] (2018). O-GlcNAc site-mapping of liver X receptor-α and O-GlcNAc transferase. Biochemical and Biophysical Research Communications - BBRC. ISSN 0006-291X. 499(2), p. 354–360. doi: 10.1016/j.bbrc.2018.03.164. Full text in Research Archive
• Moldes-Anaya, Angel; Sæther, Thomas; Uhlig, Silvio; Nebb, Hilde Irene; Larsen, Terje & Eilertsen, Hans Christian [Show all 7 contributors for this article] (2017). Two Isomeric C16 Oxo-Fatty Acids from the Diatom Chaetoceros karianus Show Dual Agonist Activity towards Human Peroxisome Proliferator-Activated Receptors (PPARs) α/γ. Marine Drugs. 15(148). doi: 10.3390/md15060148. Full text in Research Archive Show summary

  The peroxisome proliferator-activated receptors (PPARs) function as ligand-activated transcription factors that convert signals in the form of lipids to physiological responses through the activation of metabolic target genes. Due to their key roles in lipid and carbohydrate metabolism, the PPARs are important drug targets. However, for several of the PPAR drugs currently in use, adverse side effects have been reported. In an effort to identify compounds from marine organisms that may serve as molecular scaffolds for the development of novel and safer PPAR-targeting drugs, we performed a bioassay-guided screening of organic extracts made from organisms supplied by the Norwegian Biobank of Arctic Marine Organisms (Marbank). Among several interesting hits, we identified two poorly described isomeric oxo-fatty acids from the microalgae Chaetoceros karianus for which we provide the first evidence that they might display dual specificity towards human PPARα and PPARγ. Principal component analysis showed that C. karianus stood out from other Chaetoceros species, both with respect to the metabolic profile and the PPAR activity. The isolation of these compounds holds the potential of uncovering a PPAR pharmacophore with tunable activity and specificity.

• Haugen, Trine B.; Tefre, Toril; Malm, Gunilla; Jønsson, Bo AG; Rylander, Lars & Hagmar, Lars [Show all 11 contributors for this article] (2011). Differences in serum levels of CB-153 and p,p '-DDE, and reproductive parameters between men living south and north in Norway. Reproductive Toxicology. ISSN 0890-6238. 32(3), p. 261–267. doi: 10.1016/j.reprotox.2011.06.072. Full text in Research Archive
• Lorenzo, Petra Isabel O.; Brendeford, Elen Margrethe; Gilfillan, Siv; Gavrilov, Alexey A; Ledsaak, Marit & Razin, Sergey V [Show all 9 contributors for this article] (2011). Identification of c-Myb target genes in K562 cells reveals a role for c-Myb as a master regulator. Genes & cancer. ISSN 1947-6019. 2(8), p. 805–817. doi: 10.1177/1947601911428224. Full text in Research Archive Show summary

  The c-Myb transcription factor is an important regulator of hematopoietic cell development. c-Myb is expressed in immature hematopoietic cells and plays a direct role in lineage fate selection, cell cycle progression, and differentiation of myeloid as well as B- and T-lymphoid progenitor cells. As a DNA-binding transcription factor, c-Myb regulates specific gene programs through activation of target genes. Still, our understanding of these programs is incomplete. Here, we report a set of novel c-Myb target genes, identified using a combined approach: specific c-Myb knockdown by 2 different siRNAs and subsequent global expression profiling, combined with the confirmation of direct binding of c-Myb to the target promoters by ChIP assays. The combination of these 2 approaches, as well as additional validation such as cloning and testing the promoters in reporter assays, confirmed that MYADM, LMO2, GATA2, STAT5A, and IKZF1 are target genes of c-Myb. Additional studies, using chromosome conformation capture, demonstrated that c-Myb target genes may directly interact with each other, indicating that these genes may be coordinately regulated. Of the 5 novel target genes identified, 3 are transcription factors, and one is a transcriptional co-regulator, supporting a role of c-Myb as a master regulator controlling the expression of other transcriptional regulators in the hematopoietic system.

• Alm-Kristiansen, Anne Hege; Lorenzo, Petra Isabel O.; Molværsmyr, Ann-Kristin; Matre, Vilborg; Ledsaak, Marit & Sæther, Thomas [Show all 7 contributors for this article] (2011). PIAS1 interacts with FLASH and enhances its co-activation of c-Myb. Molecular Cancer. 10. doi: 10.1186/1476-4598-10-21. Full text in Research Archive Show summary

  Background FLASH is a huge nuclear protein involved in various cellular functions such as apoptosis signalling, NF-κB activation, S-phase regulation, processing of histone pre-mRNAs, and co-regulation of transcription. Recently, we identified FLASH as a co-activator of the transcription factor c-Myb and found FLASH to be tightly associated with active transcription foci. As a huge multifunctional protein, FLASH is expected to have many interaction partners, some which may shed light on its function as a transcriptional regulator. Results To find additional FLASH-associated proteins, we performed a yeast two-hybrid (Y2H) screening with FLASH as bait and identified the SUMO E3 ligase PIAS1 as an interaction partner. The association appears to involve two distinct interaction surfaces in FLASH. We verified the interaction by Y2H-mating, GST pulldowns, co-IP and ChIP. FLASH and PIAS1 were found to co-localize in nuclear speckles. Functional assays revealed that PIAS1 enhances the intrinsic transcriptional activity of FLASH in a RING finger-dependent manner. Furthermore, PIAS1 also augments the specific activity of c-Myb, and cooperates with FLASH to further co-activate c-Myb. The three proteins, FLASH, PIAS1, and c-Myb, are all co-localized with active RNA polymerase II foci, resembling transcription factories. Conclusions We conclude that PIAS1 is a common partner for two cancer-related nuclear factors, c-Myb and FLASH. Our results point to a functional cooperation between FLASH and PIAS1 in the enhancement of c-Myb activity in active nuclear foci.

• Sæther, Thomas; Pattabiraman, D.R.; Alm-Kristiansen, Anne Hege; Kielland, Linn Troye Vogt-; Gonda, T.J. & Gabrielsen, Odd Stokke (2011). A functional SUMO-interacting motif in the transactivation domain of c-Myb regulates its myeloid transforming ability. Oncogene. ISSN 0950-9232. 30(2), p. 212–222. doi: 10.1038/onc.2010.397. Full text in Research Archive
• Molværsmyr, Ann-Kristin; Sæther, Thomas; Gilfillan, Siv; Lorenzo, Petra Isabel O.; Kvaløy, Heidi & Matre, Vilborg [Show all 7 contributors for this article] (2010). A SUMO-regulated activation function controls synergy of c-Myb through a repressor-activator switch leading to differential p300 recruitment. Nucleic Acids Research (NAR). ISSN 0305-1048. 38(15), p. 4970–4984. doi: 10.1093/nar/gkq245. Full text in Research Archive
• Rylander, Lars; Wetterstrand, Boel; Haugen, Trine B.; Malm, Gunilla; Malm, Johan & Bjørsvik, Cathrine [Show all 9 contributors for this article] (2009). Single semen analysis as a predictor of semen quality: clinical and epidemiological implications. Asian Journal of Andrology (AJA). ISSN 1008-682X. 11(6), p. 723–730. doi: 10.1038/aja.2009.64. Full text in Research Archive
• Alm-Kristiansen, Anne Hege; Sæther, Thomas; Matre, Vilborg; Otnæss, Siv Kolstø; Dahle, Øyvind & Gabrielsen, Odd Stokke (2008). FLASH acts as a co-activator of the transcription factor c-Myb and localizes to active RNA polymerase II foci. Oncogene. ISSN 0950-9232. 27, p. 4644–4656. doi: 10.1038/onc.2008.105. Full text in Research Archive
• Sæther, Thomas; Berge, T; Ledsaak, Marit; Matre, Vilborg; Alm-Kristiansen, Anne Hege & Dahle, O [Show all 8 contributors for this article] (2007). The chromatin remodeling factor Mi-2 alpha acts as a novel co-activator for human c-Myb. Journal of Biological Chemistry. ISSN 0021-9258. 282. doi: 10.1074/jbc.M700755200. Full text in Research Archive
• Sæther, Thomas; Tran, TN; Rootwelt, H; Grav, HJ; Christophersen, BO & Haugen, Trine B. (2007). Essential fatty acid deficiency induces fatty acid desaturase expression in rat epididymis, but not in testis. Reproduction. ISSN 1470-1626. 133(2), p. 467–477. doi: 10.1530/REP-06-00294. Full text in Research Archive
• Berge, Tone; Matre, Vilborg; Brendeford, Elen Margrethe; Sæther, Thomas; Lüscher, Bernhard & Gabrielsen, Odd Stokke (2007). Revisiting a selection of target genes for the hematopoietic transcription factor c-Myb using chromatin immunoprecipitaion and c-Myb knockdown. Blood Cells, Molecules & Diseases. ISSN 1079-9796. 39(3), p. 278–286. doi: 10.1016/j.bcmd.2007.05.007. Full text in Research Archive
• Ruhayel, Yasir; Malm, Gunilla; Haugen, Trine B.; Henrichsen, Trine; Bjørsvik, Cathrine & Grotmol, Tom [Show all 12 contributors for this article] (2007). Seasonal variation in serum concentrations of reproductive hormones and urinary excretion of 6-sulfatoxymelatonin in men living north and south of the Arctic Circle: a longitudinal study. Clinical Endocrinology. ISSN 0300-0664. 67. doi: 10.1111/j.1365-2265.2007.02843.x. Full text in Research Archive
• Aschim, Elin L.; Sæther, Thomas; Wiger, Richard; Grotmol, Tom & Haugen, Trine B. (2004). Differential distribution of splice variants of estrogen receptor β in human testicular cells suggests specific functions in spermatogenesis. Journal of Steroid Biochemistry and Molecular Biology. ISSN 0960-0760. 92(1-2), p. 97–106. doi: 10.1016/j.jsbmb.2004.05.008. Full text in Research Archive
• Malm, Gunilla; Haugen, Trine B.; Henrichsen, Trine; Bjørsvik, Cathrine; Grotmol, Tom & Sæther, Thomas [Show all 12 contributors for this article] (2004). Reproductive function during summer and winter in Norwegian men living north and south of the Arctic Circle. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 89(9), p. 4397–4402. doi: 10.1210/jc.2004-0427. Full text in Research Archive
• Sæther, Thomas; Tran, Thien Ngoc; Rootwelt, Helge; Christophersen, Bjørn & Haugen, Trine B. (2003). Expression and Regulation of delta 5-Desaturase, delta 6-Desaturase, Stearoyl-Coenzyme A (CoA) Desaturase 1, and Stearoyl-CoA Desaturase 2 in Rat Testis. Biology of Reproduction. ISSN 0006-3363. 69, p. 117–124. doi: 10.1095/biolreprod.102.014035. Full text in Research Archive

View all works in NVA

• Hjorth, Marit; Doncheva, Atanaska Ivanova; Norheim, Frode Amador; Ulven, Stine Marie; Holven, Kirsten Bjørklund & Sæther, Thomas [Show all 7 contributors for this article] (2022). Consumption of salmon fishmeal increases hepatic cholesterol content in obese C57BL/6J mice. Full text in Research Archive
• Sæther, Thomas (2021). Muliggjørende bioteknologi - hva vi kan gjøre med den, og hva den kan gjøre med oss. Full text in Research Archive
• Heggøy, Oddvar; Shimmings, Paul; Nordsteien, Ola & Sæther, Thomas (2020). Magert med lappspurv i 2020. Vår Fuglefauna. ISSN 0332-5601. 43(4), p. 210–216. Full text in Research Archive Show summary

  Da NOF valgte lappspurv som Årets fugl i 2020, oppfordret vi til en nasjonal kartlegging av artens hekkeområder. Målet var å finne ut mer om endringer i antall og forekomst. Både korona og mengder av snø gjorde året spesielt. Likevel ble ny og spennende kunnskap om arten samlet inn.

• Holven, Kirsten Bjørklund; Sæther, Thomas; Hjorth, Marit; Dalen, Knut Tomas; Ulven, Stine Marie & Ottestad, Inger [Show all 7 contributors for this article] (2019). Kan fisk utnyttes enda mer og samtidig fremme folkehelsen? Norsk tidsskrift for ernæring (NTFE). ISSN 1503-5034. 17(2), p. 20–22. Full text in Research Archive
• Fan, Qiong; Nørgaard, Rikke Christine; Grytten, Ivar; Ness, Cecilie Maria; Lucas, Christin & Vekterud, Kristin [Show all 15 contributors for this article] (2019). LXRα interacts with the glucose-sensing transcription factor ChREBPα to regulate its transcriptional activity. Full text in Research Archive Show summary

  The cholesterol-sensing nuclear receptor Liver X Receptor (LXR) and the glucose-sensing transcription factor carbohydrate responsive element-binding protein (ChREBP) are central players in the regulation of glucose and lipid metabolism. LXR does this job in part by regulating the expression of ChREBP. We have previously shown that LXR also regulates ChREBP activity. To get a better understanding of mechanisms at play, we asked if LXR and ChREBP interact physically. Interestingly, LXRα binds to ChREBPα, but not the shorter isoform ChREBPβ. Co-immunoprecipitation (CoIP) of different LXR and ChRBEP domains shows that it is ChREBPα’s low glucose inhibitory domain (LID), which is lacking in ChREBPβ, that interacts with the ligand-binding domain (LBD) of LXRα. In line with this, we see a surprisingly high co-occupancy of LXR and ChREBP on regulatory regions in the mouse genome when re-analysing two independently published chromatin immunoprecipitation-sequencing (ChIP-seq) datasets. Moreover, Functional studies show that LXRα is able to co-activate together with ChREBPα, but not ChREBPβ, and increase ChREBP-specific target gene expression in vitro and in vivo. Unexpectedly however, ligand-engaged LXR exhibits a repressive effect on the expression of the same genes in primary mouse hepatocytes, in contrast to what we observe with target genes that are common to LXR and ChREBP. Performing CoIP and ChIP on selected target genes, we demonstrate mechanistically that the repressive effect most likely is due to a weakened ChREBPα:LXRα interaction and reduced binding of ChREBP to chromatin. Altogether, the novel transcriptional complex comprising ChREBPα and LXRα adds to the intricate integration of nutrient signals in glucose and lipid metabolism.

• Sæther, Thomas; Ingvaldsen, Christoffer Aam & Lundby, Marit (2019). Denne fuglen er symbolet på det rike fuglelivet i Romerikes Amazonas. Nå er den i ferd med å forsvinne. [Journal]. Romerikes Blad. Full text in Research Archive Show summary

  Store deler av fuglebestandene i Nordre Øyeren Naturreservat er i ferd med å kollapse. Ved Nordre Øyeren fuglestasjon viser de siste tellingene at situasjonen er verre enn de fryktet.

• Fan, Qiong; Nørgaard, Rikke Christine; Ulven, Stine Marie; Lucas, Christin; Bindesbøll, Christian & Grønning-Wang, Line Mariann [Show all 8 contributors for this article] (2018). Exploring the functional importance of a transcriptional cholesterol/sugar switch in liver. Full text in Research Archive
• Fan, Qiong; Nørgaard, Rikke Christine; Grytten, Ivar; Ulven, Stine Marie; Lucas, Christin & Bindesbøll, Christian [Show all 11 contributors for this article] (2018). LXRα interacts with the glucose-sensing transcription factor ChREBPα and increases its transcriptional activity. Full text in Research Archive
• Sæther, Thomas (2018). Digging into the ocean’s molecular treasure trove: Marine bioprospecting for anti-diabetic activities. Full text in Research Archive
• Sæther, Thomas (2017). Havets hemmeligheter. [Internet]. UiOs Facebook-side. Full text in Research Archive Show summary

  «Havets hemmeligheter» - en del av UiOs «Kom til poenget»-kampanje. Diabetes rammer stadig flere mennesker. En viktig årsak til dette er vår livsstil: Vi spiser usunt og beveger oss mindre. Mange mennesker med diabetes må ta medisiner. Noen av disse medisinene har ekle bieffekter. Sammen med forskere i Tromsø har vi lett etter molekyler - i havet - som kan brukes til å lage ny og trygg diabetesmedisin. Vi fant to spennende forbindelser - i en liten alge. Sammen med forskere ved Farmasøytisk institutt forsøker vi å forberede stoffene slik at de kan brukes som medisin.

• Nørgaard, Rikke Christine; Fan, Qiong; Lucas, Christin; Grønning-Wang, Line Mariann; Nebb, Hilde Irene & Sæther, Thomas (2017). LXRα interacts with the glucose-sensing transcription factor ChREBPα and increases its transcriptional activity. Full text in Research Archive
• Sæther, Thomas; Moldes-Anaya, Angel; Tungen, Jørn Eivind; Vik, Anders; Paulsen, Steinar M & Sylte, Ingebrigt [Show all 8 contributors for this article] (2016). Anti-diabetic activity from marine lipids: new anti-diabetic drugs. Full text in Research Archive
• Sæther, Thomas; Moldes-Anaya, Angel; Tungen, Jørn Eivind; Vik, Anders; Paulsen, Steinar Martin & Sylte, Ingebrigt [Show all 8 contributors for this article] (2015). Anti-diabetic activity from marine lipids: new anti-diabetic drugs. Full text in Research Archive
• Sæther, Thomas (2014). Anti-diabetic activity from marine lipids (ADAM): New anti-diabetic drugs. Full text in Research Archive
• Sæther, Thomas; Moldes-Anaya, Angel; Norrheim-Larsen, Laila; Larsen, Terje; Paulsen, Steinar M & Nebb, Hilde Irene (2014). Two near identical oxylipins from the diatom Chaetoceros karianus show isoform-specific agonist activity towards human peroxisome proliferator-activated receptors (PPARs). Full text in Research Archive
• Moldes-Anaya, Angel; Sæther, Thomas; Larsen, Laila Norrheim; Larsen, Terje; Nebb, Hilde Irene & Paulsen, Steinar (2013). Identifying natural products with agonist activity against human nuclear receptors in extracts of cultured marine microalgae. Full text in Research Archive
• Moldes-Anaya, Angel; Sæther, Thomas; Norrheim-Larsen, Laila; Nebb, Hilde Irene; Larsen, Terje & Paulsen, Steinar (2013). Identifying natural products with agonist or modulatory activity against human nuclear receptors in extracts from cultured marine microalgae. Full text in Research Archive
• Bindesbøll, Christian; Fan, Qiong; Sæther, Thomas; Dalen, Knut Tomas; Nebb, Hilde Irene & Grønning-Wang, Line Mariann (2013). Nuclear receptors as targets for treatment and prevention of metabolic diseases. Full text in Research Archive Show summary

  Obesity, type 2 diabetes (T2D) and its associated comorbidity atherosclerosis are the leading cause of mortality in the Western world. A major consequence of obesity is insulin resistance, which is strongly associated with deposition of fat and uncontrolled glucose production in the liver, thereby contributing to the development of T2D. Peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs) are lipid-activated nuclear receptors (NRs) that through target gene activation regulate systemic glucose and lipid metabolism, control cholesterol transport, and modulate inflammation within the vascular wall. The NR Group at the Department of Nutrition, UoO studies the LXRs and PPARs in cross-talk with signaling pathways activated by lipids, insulin and glucose. We have recently shown that LXRalpha and LXRbeta are targets for glucose-hexosamine-derived OGlcNAc modification in liver and macrophages. Importantly, induction of LXRa O-GlcNAcylation by high carbohydrate feeding coincides with increased expression of the lipogenic gene SREBP-1c. This intriguing observation gives insight into novel aspects of LXR activation, and suggests LXR to be an important mediator of sugar-induced hepatic fat deposition and insulin resistance. Our ultimate goal is to gain new understanding of the role of LXRs and PPARs in the development of diet-induced metabolic diseases and to identify and develop specific ligands from marine microalgae for the treatment of metabolic disease.

• Matre, Vilborg; Aabel, Linn Ingeborg; Ledsaak, Marit; Vollsund, Pernille; Sæther, Thomas & Gabrielsen, Odd Stokke (2013). PTM-crosstalk: SUMO1 acts as a docking domain for the nuclear kinase HIPK1 mediating SUMO-linked phosphorylation of c-Myb and other targets. Full text in Research Archive Show summary

  Like histones, many transcription factors (TFs) are modified at multiple sites by a diverse set of posttranslational modifications (PTMs) such as phosphorylation, acetylation, methylation, and sumoylation. PTMs are believed to be linked ("TF code") through crosstalk. A classical scenario of PTM-crosstalk is that one specific PTM acts as a docking site for a modification enzyme introducing another PTM. SUMO (small ubiquitin-like modifier) conjugated to TFs is a reversible PTM that modulates the function and/or interactions of the TFs. Here we focus on how SUMO may induce other PTMs in TFs. Our model is the transcription factor c-Myb and the nuclear homeodomain-interacting protein kinases (HJPKl and HJPK2). We have previously identified HIPK1 as an interaction partner for c-Myb (Matre et al, 2009). The function of c-Myb is largely affected by SUMO-conjugation (Molværsmyr et al, 2010) and SUMO-binding (Sæther et al. 2011). Here, we have studied c-Myb PTM-crosstalk by investigating the link between SUMO-conjugation and phosphorylation. We conclude that SUMO conjugated to c-Myb directs the recruitment of HIPK1, making the sumoylated protein the preferred kinase substrate. The SUMO-binding property of HIPK1 is dependent on an active kinase domain. The SUMO-docking property extends to HIPK2 and CtBP1. This work reveals a novel mechanism for PTM-crosstalk on TFs.

• Sæther, Thomas; Moldes-Anaya, Angel; Larsen, Laila Norrheim; Larsen, Terje; Paulsen, Steinar & Nebb, Hilde Irene (2013). Identifying natural products with agonist activity against human nuclear receptors in extracts of cultured marine microalgae. Full text in Research Archive Show summary

  Nuclear receptors (NRs) are highly conserved transcription factors that regulate transcription in response to small lipophilic molecules. These receptors regulate the expression of genes involved in many critical processes such as embryonic development, metabolism and inflammation. Dysfunctional signalling of NRs is thought to be involved in diseases such as cancer, type 2 diabetes, obesity and dyslipidemia. All these facts make NRs attractive targets for pharmacological intervention and development of therapeutics. Several NR ligands with well-recognised biological effects are in clinical use, like the hypolipidemic fibrates (e.g. Tricor), acting as peroxisome proliferator-activated receptors alpha (PPARα) activators, and the anti-diabetic thiazolidinediones (e.g. Avandia), targeting PPARγ. However, the negative side effects reported for thiazolidinediones points to the need of finding new medicines for treating diseases like type 2 diabetes. A bioassay guided strategy on identification, purification and characterisation of PPAR ligands from cultured microalgae is presented here. We are making use of biologically assay systems incorporating unique protein targets to identify secondary metabolites possessing desirable pharmacological profile from extract generated from microalgae cultures. We have identified PPAR agonist activity in organic extracts from xenic cultures of marine diatoms.

• Sæther, Thomas; Moldes-Anaya, Angel; Norrheim-Larsen, Laila; Larsen, Terje; Paulsen, Steinar M & Nebb, Hilde Irene (2013). Identifying natural products with agonist activity against human nuclear receptors in extracts of cultured marine microalgae. Full text in Research Archive
• Molværsmyr, Ann-Kristin; Ledsaak, Marit; Alm-Kristiansen, Anne Hege; Lorenzo, Petra Isabel O.; Matre, Vilborg & Sæther, Thomas [Show all 7 contributors for this article] (2012). The SUMO E3 ligase PIAS1 interacts with c-Myb and enhances its transcriptional activity. Full text in Research Archive Show summary

  PIAS1 belongs to the family of Protein Inhibitor of Activated STAT. In addition to their function as negative regulators of STAT signaling, PIAS proteins also act as SUMO E3 ligases, enhancing sumoylation of target proteins. This activity is dependent on a RING finger domain present in PIAS proteins. Even though sumoylation of trancriptional regulators often leads to inhibition of their activity, PIAS proteins are known to act as both negative and positive regulators of transcription, in both SUMO-dependent or independent manners. We have previously identified FLASH (FLICE associated huge protein) as a co-activator of the transcription factor c-Myb. To find additional FLASH-associated proteins, we performed a yeast two-hybrid screening with FLASH as bait, and identified the SUMO E3 ligase PIAS1 as an interacting partner. Functional assays revealed that PIAS1 enhances FLASH's activity and its ability to co-activate c-Myb in a RING finger-dependent manner. The three proteins, FLASH, PIAS1, and c-Myb, are all co-localized with active RNA polymerase II foci. As an E3 ligase we expect PIAS1 to sumoylate c-Myb and inhibit the transcriptional activity of c-Myb. Contrarily, we only see weak sumoylation of c-Myb and an enhancement of c-Myb transactivation. We are currently studying the involvement of p300 in the PIAS1 enhancement of c-Myb transcriptional activity. We suggest that the RING finger domain of PIAS1 have two functions, one being a SUMO E3 ligase and another recruiting the co-activator p300.

• Sæther, Thomas; Bengtsen, Mads; Molværsmyr, Ann-Kristin; Pattabiraman, D.R.; Alm-Kristiansen, Anne Hege & Ledsaak, Marit [Show all 8 contributors for this article] (2012). Regulating the regulator: SUMO functions as a master switch for the transcription factor c-Myb. Full text in Research Archive Show summary

  The oncoprotein c-Myb is an essential hematopoietic transcription factor that controls proliferation and differentiation of progenitors during blood cell development. This transcriptional activator plays a direct role in lineage fate selection, cell cycle progression, and differentiation of myeloid as well as B- and T-lymphoid progenitors. Recent studies have shown that c-Myb accomplishes this by controlling the expression of several important hematopoietic transcriptions factors, and in that way acts as a master regulator. c-Myb is modified by SUMO on two lysines in its C-terminal regulatory domain (CRD), and is able to bind SUMO via a SUMO-interacting motif (SIM) in the central transactivation domain. Both these SUMO-contacts are important in regulating the transactivation activity of c-Myb, and breaking these contacts makes c-Myb super active. We have found that the ability of c-Myb to synergize with other transcription factors on compound promoters is restricted by synergy control, linked to the SUMOylation of CRD. De-SUMOylation of c-Myb leads to a dramatic change in synergy behavior, which correlates with a SUMO-dependent differential recruitment of p300 and a corresponding local change in histone H3 and H4 acetylation. Using cell-based transformation assays, we have addressed the abilities of c-Myb SUMO binding and conjugation mutants to transform hematopoietic cells. Interestingly, only loss of SUMO binding, and not SUMO conjugation, enhances the myeloid transformational potential of c-Myb. c-Myb with the SIM mutated confers a high proliferative ability and causes an effective differentiation block. This establishes SUMO binding as a mechanism responsible for keeping the transforming potential of the oncoprotein in check. Taken together this implies that SUMO functions as a master regulatory switch for c-Myb. Given that the SUMO-system may be perturbed in different cancers, c-Myb may be particularly vulnerable to such changes and thus mediate dramatic downstream effects.

• Matre, Vilborg; Aabel, Linn Ingeborg; Ledsaak, Marit; Vollsund, Pernille; Sæther, Thomas & Gabrielsen, Odd Stokke (2012). PTM-crosstalk: SUMO1 acts as a docking domain for the nuclear kinase HIPK1 mediating SUMO-linked phosphorylation of c-Myb and other targets. Full text in Research Archive
• Sæther, Thomas; Molværsmyr, Ann-Kristin; Gilfillan, Siv; Alm-Kristiansen, Anne Hege; Aabel, Linn Ingeborg & Matre, Vilborg [Show all 7 contributors for this article] (2011). The hematopoietic transcription factor c-Myb functions as an epigenetic organizer. Full text in Research Archive Show summary

  The c-Myb protein belongs to a group of early hematopoietic transcription factors that are important for progenitor generation and proliferation. These factors have been hypothesized to participate in establishing epigenetic patterns specific for hematopoietic genes. Consistent with its role as a regulator of stem and progenitor cells, a picture is now emerging where c-Myb appears to be directly involved in chromatin modulation. Several lines of evidence, both from our lab and others, point to a particular involvement of c-Myb in histone interaction and chromatin modification. Importantly, the DNA-binding domain of c-Myb not only binds DNA. Its SANT properties also enables it to bind to the N-terminal tail of histone H3 and facilitates histone acetylation by p300. We show that SUMOylation of c-Myb causes differential recruitment of p300 to chromatin leading to a local change in histone H3 and H4 acetylation, supporting the hypothesis of SUMO as a determinant of chromatin signatures. p300/CBP was the first chromatin modifying enzyme demonstrated to be recruited to regulatory gene elements by c-Myb. Today the catalogue also includes MLL, PIAS1, HIPK1, and Mi-2, all of which have enzymatic activity. Together with FLASH and PIAS1, c-Myb also co-localizes with active RNA polymerase II foci, resembling transcription factories. The aim of the present work in to define a specific Myb-induced epigenetic signature by correlating the recruitment of these co-factors with histone marks on Myb-regulated genomic elements.

• Sæther, Thomas; Molværsmyr, Ann-Kristin; Lorenzo, Petra Isabel O.; Gilfillan, Siv; Kvaløy, Heidi & Matre, Vilborg [Show all 7 contributors for this article] (2010). A SUMO-regulated activation function (SRAF) controls synergy of c-Myb through a repressor-activator switch. Full text in Research Archive Show summary

  Synergy between transcription factors is a well-known phenomenon. An interesting twist to the phenomenon of synergy was the identification of a short protein motif that restricted activator synergy and mediated “synergy control” (SC). Notably, SC motifs turned out to be sites of SUMO-conjugation, and sumoylation was shown to disrupt synergy. The transcription factor c-Myb plays a key role in controlling gene programs during proliferation and differentiation of hematopoietic cells. Several target genes are activated by c-Myb in synergy with other transcription factors, and c-Myb activity is regulated by sumoylation. In the present work we investigate the effect of sumoylation of c-Myb on its synergistic capacity. We find evidence for a strong SUMO-governed synergy control of the factor. Moreover, we make observations that point to a more general mechanism underlying the control of transcriptional synergy. In our mechanistic model the restriction of activating functions (AFs) through sumoylation is a central aspect.

• Sæther, Thomas; Pattabiraman, D.R.; Aabel, Linn Ingeborg; Matre, Vilborg; Gonda, T.J. & Gabrielsen, Odd Stokke (2010). A functional SUMO-interacting motif in the transactivation domain of c-Myb regulates its myeloid transforming ability. Full text in Research Archive Show summary

  c-Myb is an essential hematopoietic transcription factor that controls proliferation and differentiation of progenitors during blood cell development. Sumoylation of the C-terminal regulatory domain (CRD) is known to have a major impact on the activity of c-Myb. Recently, our lab has identified several interaction partners of c-Myb. Curiously, all these partners are in one way or another linked to the SUMO-system. In this work, we address a novel SUMO-link of c-Myb, non-covalent binding of SUMO to c-Myb. Based on the consensus SUMO-interacting motif (SIM) we identified and examined putative SIMs in human c-Myb. The analysis shown below establishes SUMO binding as a mechanism involved in modulating the transactivation activity of c-Myb, and responsible for keeping the transforming potential of the oncoprotein in check.

• Rangberg, Anbjørg; Sæther, Thomas & Gabrielsen, Odd Stokke (2010). Design of a system for inducible SUMOylation of the transcription factor c-Myb. Full text in Research Archive Show summary

  c-Myb is a transcription factor involved in proliferation and differentiation of hematopoietic progenitor cells. Its activity is regulated by post-translational modifications, including SUMOylation. SUMO (Small Ubiquitin-related Modifier) is covalently conjugated to two specific lysines in c-Myb located in its negative regulatory domain (K503 and K527). Its transactivating potential is severely reduced, even when only a small portion of Myb is SUMOylated. To study the dynamics of c-Myb SUMOylation we have designed a system for inducible SUMOylation inspired by the USDDS method. SUMO is conjugated to targets in a process involving three different enzymes, one of these being the SUMO-conjugating enzyme Ubc9. By bringing Ubc9 and c-Myb together in vivo the level of SUMOylated c-Myb increases. We have taken advantage of the inducible heterodimerization system from ARIAD (www.ariad.com/wt/tertiarypage/kits_info). In dimerization-dependent SUMOylation, c-Myb and Ubc9 are fused to the chemically activatable heterodimerization domains FKBP and FRB respectively. By addition of a small “dimerizer” (rapamycin derivate) the fusion proteins are brought together and SUMO-modification induced. We have established and validated this system in living cells, and are now addressing biologically relevant questions with regard to c-Myb and SUMO. Inducible chimeras might prove to be a valuable tool for the study of posttranslational modifications in general.

• Vollsund, Pernille; Bergholtz, Stine Louise; Sæther, Thomas; Aasland, Rein & Gabrielsen, Odd Stokke (2009). Understanding the phosphorylation-sumoylation cross talk in the transcription factor c-Myb. Full text in Research Archive Show summary

  The transcription factor c-Myb is involved in proliferation and differentiation of hematopoietic cells. c-Myb is regulated by several post-translational modifications (PTMs), including phosphorylation and sumoylation. SUMO (small ubiquitin related modifier) modifies the target protein by covalent conjugation to specific lysines. Previous studies from our group described sumoylation of c-Myb at two sites (K503 and K527) in its negative regulatory domain (NRD) causing severely reduced activity1 . SUMO-conjugation mainly modulates the ability of c-Myb to synergize on complex promoters2. Various phosphorylations of c-Myb have also been reported3,4. Preliminary results indicated that sumoylation and phosphorylation might be closely linked, suggesting a PTM crosstalk. Hence, a series of mutants were made to establish if there is a dependency between these modifications or if they are independent. The preliminary data reported here are mainly based on analysis of migration shifts after phosphatase treatments.

• Sæther, Thomas; Molværsmyr, Ann-Kristin; Lorenzo, Petra Isabel O.; Kvaløy, Heidi; Matre, Vilborg & Gabrielsen, Odd Stokke (2009). A SUMO-regulated activation function (SRAF) controls synergy of c-Myb through a repressor-activator switch. Full text in Research Archive Show summary

  Synergy between transcription factors operating together on complex promoters is a key aspect of gene activation. The ability of specific factors to synergize is restricted by sumoylation (synergy control). Focusing on the hematopoietic transcription factor c-Myb, we found evidence for a strong synergy control linked to SUMO-conjugation in its negative regulatory domain (NRD), while AMV v-Myb had escaped synergy control. Mechanistic studies revealed a SUMO-dependent switch in the function of NRD. When NRD is sumoylated, it reduces the activity of c-Myb. When sumoylation is abolished, the function of NRD switches into being activating, providing the factor with a second activation function (AF). Thus c-Myb harbours two AFs, one constitutively active and one in NRD being SUMO-regulated (SRAF). This double AF augments c-Myb synergy at compound natural promoters. A similar SUMO-dependent switch was observed in the C-terminal regulatory domain of p53. We therefore propose a general model for SUMO-mediated synergy control. In this model, SUMO controls synergy by determining the number and strength of AFs associated with a promoter through the bound transcription factors.

• Sæther, Thomas; Molværsmyr, Ann-Kristin; Matre, Vilborg; Lorenzo, Petra Isabel O. & Gabrielsen, Odd Stokke (2008). SUMO-conjugation of the transcription factor c-Myb controls cooperative behaviour and induces an activator-to-repressor switch in the negative regulatory domain. Full text in Research Archive Show summary

  The transcription factor c-Myb plays a key role in controlling gene programs during proliferation and differentiation of hematopoietic cells. Several target genes are activated by c-Myb in synergy with other transcription factors. It has been reported that the ability of specific factors to synergize is restricted by sumoylation (synergy control). Since c-Myb is being sumoylated, we investigated the effect of sumoylation of c-Myb on its synergistic capacity. By using a set of dedicated reporters to quantify its synergy behaviour, we found evidence for a strong synergy control linked to SUMO-conjugation in the negative regulatory domain (NRD) of c-Myb. Interestingly, the oncogenic version of c-Myb, AMV v-Myb, lacking most of the NRD including two SUMO-conjugation sites, appears to have escaped synergy control, as judged by the high synergy factor measured. The search for a mechanism revealed a SUMO-dependent switch in the function of NRD. When NRD is sumoylated, it acts negatively by reducing the activity of c-Myb. When sumoylation is abolished, NRD switches into a transactivation domain (TAD), providing the factor with a second TAD. This implies a new picture of c-Myb having two TADs, one centrally located and constitutively active and one in NRD being under SUMO-control. We observed that this increase in the number of TADs augments c-Myb synergy at compound natural promoters as predicted. Furthermore, we suggest that this SUMO-dependent switch mechanism is not specific for c-Myb, since we observed a similar switch when we analyzed the effect of sumoylation in the C-terminal regulatory domain of p53. We therefore propose a general model for SUMO-mediated synergy control in which SUMO restrains the number of active TADs and thus the available co-activator interaction surfaces. In this model, SUMO controls synergy by determining the number and strength of independent and active TADs associated with a promoter through the bound transcription factors.

• Molværsmyr, Ann-Kristin; Kvaløy, Heidi; Sæther, Thomas; Matre, Vilborg & Gabrielsen, Odd Stokke (2007). Controlling gene expression through SUMO-conjugation - the importance of synergy. Full text in Research Archive Show summary

  Synergy control (SC) is a concept attributed to a short motif (PsiKxE) found in a number of nuclear regulators, acting to limit their transcriptional synergy. Disruption of this motif enhances synergistic activation at compound response elements, without altering the activity driven from a single site. Since SC motifs were found to be identical to sumoylation sites, the research has been focused on SUMO as a repressive modifier per se. We believe that the multiplicity aspect of the SC-motifs is not sufficiently appreciated in the current understanding of how SUMO controls transcriptional processes. We have found that SC is strongly operating on the oncoprotein c-Myb. By using reporters with variable numbers of MREs, we have observed that the level of synergy appears to be highly dependent on whether c-Myb can be sumoylated or not. Studies on v-Myb, the oncogenic version of c-Myb which cannot be sumoylated, imply that escape from SC might be part of an oncogenic strategy. Working with this model, we unexpectedly came across a conditional transactivation domain (TAD), embedded within c-Myb’s traditionally described negative regulatory domain (NRD). When tethering c-Myb NRD to a Gal4 responsive reporter, this domain switches from repressing to strongly activating transcription, when sumoylation is abrogated by mutating the SC motif. The mechanism and precise location of this switchable TAD are currently being studied. Furthermore, an exciting feature of the SUMO-switchable TAD construct is the possibility to monitor the efficiency or equilibrium of the SUMO conjugation/de-conjugation apparatus in the cell. This is now being tested.

• Sæther, Thomas; Berge, Tone; Ledsaak, Marit; Matre, Vilborg; Alm-Kristiansen, Anne Hege & Dahle, Øyvind [Show all 8 contributors for this article] (2007). The chromatin remodelling factor Mi-2alpha acts as a novel co-activator for human c-Myb. Full text in Research Archive Show summary

  The c-Myb protein belongs to a group of early hematopoietic transcription factors that are important for progenitor generation and proliferation. These factors have been hypothesized to participate in establishing chromatin patterns specific for hematopoietic genes. In a two-hybrid screening we identified the chromatin remodelling factor Mi-2alpha as an interaction partner for human c-Myb. The main interacting domains were mapped to the N-terminal region of Mi-2alpha and the DNA-binding domain of c-Myb. Surprisingly, functional analysis revealed that Mi-2alpha previously studied as a subunit in the NuRD co-repressor complex, enhanced c-Myb dependent reporter activation. Consistently, knock-down of endogenous Mi-2alpha in c-Myb expressing K562 cells led to down-regulation of the c-Myb target genes NMU and ADA. When wild-type and helicase-dead Mi-2alpha were compared, the Myb-Mi-2alpha co-activation appeared to be independent of the ATPase/DNA helicase activity of Mi-2alpha. The rationale for the unexpected co-activator function seems to lie in a dual function of Mi-2alpha, by which this factor is able to repress transcription in a helicase-dependent and activate in a helicase-independent fashion, as revealed by Gal4 tethering experiments. Interestingly, desumoylation of c-Myb potentiated the Myb-Mi-2alpha transactivational co-operation, as did cotransfection with p300.

• Alm-Kristiansen, Anne Hege; Sæther, Thomas; Ledsaak, Marit; Matre, Vilborg & Gabrielsen, Odd Stokke (2006). FLASH is a coregulator of the transcription factor c-Myb. Full text in Research Archive
• Sæther, Thomas; Tran, Thien N.; Rootwelt, Helge; Grav, Hans J.; Christophersen, Bjørn O. & Haugen, Trine B. (2006). Desaturase expression, lipid profile, and sperm morphology are differently affected by fat free diet in cauda and caput epididymis in the rat. Full text in Research Archive
• Sæther, Thomas; Berge, Tone; Ledsaak, Marit; Dahle, Øyvind; Matre, Vilborg & Lüscher, Bernhard [Show all 7 contributors for this article] (2004). Human c-Myb interacts with the Mi-2alpha subunit of the NuRD complex. Full text in Research Archive Show summary

  The c-Myb protein belongs to a group of ´early´ haematopoietic transcription factors that are important for progenitor generation and proliferation. These factors have been hypothesized to participate in establishing chromatin patterns specific for haematopoietic genes [Muller and Leutz (2001) Curr Opin Genet Dev 11, 167-174]. In a two-hybrid screen, we identified Mi-2alpha as an interaction partner for human c-Myb. Mi-2alpha is a member of the NuRD (Nucleosome Remodelling and histone Deacetylase) co-repressor complex and responsible for its chromatin remodelling activity. Using various interaction assays, we confirmed the association and mapped the main interacting domains to the C-terminal region of Mi-2alpha (aa 1653-2000) and the FAETL region (leucin-rich; aa. 352-417) of c-Myb. Myb shows affinity for the entire NuRD complex as revealed by analysis of other components of the complex; in transfected cells we detected association between c-Myb and HDAC1, and from Jurkat nuclear extracts we pulled down endogenous c-Myb using antibodies against MTA2 and RbAp46. Functional analysis revealed that while the C-terminal interaction domain in Mi-2alpha decreased c-Myb´s DNA binding and inhibited Myb-dependent reporter-activation, the full-length Mi-2alpha apparently enhanced c-Myb dependent reporter activation, a phenomenon that seems to be related to Mi-2alpha stabilizing the c-Myb protein. The link between SUMO-1 modification of c-Myb and Mi-2alpha interaction is currently being addressed. Overall, our results point to the direct involvement of c-Myb in the restructuring of chromatin through its interaction with the NuRD complex.

• Ruhayel, Yasir; Malm, Gunilla; Haugen, Trine B.; Henrichsen, Trine; Bjørsvik, Cathrine & Grotmol, Tom [Show all 13 contributors for this article] (2004). Seasonal Variation in Melatonin, Reproductive Hormones and Semen Parameters in Men living North and South of the Arctic Circle. Full text in Research Archive
• Sæther, Thomas; Christophersen, Bjørn O. & Haugen, Trine B. (2004). Essential fatty acid deficiency does not induce desaturases in testis, like in epididymis and liver. Full text in Research Archive
• Sæther, Thomas (2003). Lipid Dynamics And Sperm Function. Full text in Research Archive Show summary

  The content and distribution of lipids in the mammalian germ cell, change in an ordered fashion from the first stem cell division, through spermatogenesis and epididymal maturation, to capacitation and fusion with the oocyte in the female genital tract. During these changes, two important, yet contradictory, requirements of the germ cell are to be met: preservation of the genome integrity and acquisition of fusibility. Testicular cells, especially the germ cells, are rich in polyunsaturated fatty (PUFAs) with different fatty acids dominating depending on the species. The rodent testis has a high content of Osbond acid, 22:5(n-6), whereas docosahexaenoic acid, 22:6(n-3), is dominating in primates. In the progression of germ cell differentiation from spermatogonium to condensing spermatid in mouse, the relative amount of 22:5(n-6) increases from 2 to 20%. Through studies of both enzyme activity and gene expression we have located delta5-, delta6- and delta9-desaturase – members of the PUFA desaturation/elongation apparatus – to the Sertoli cells. These desaturases are induced by FSH. Most of the PUFAs in the testis are incorporated in lipids, and since the desaturase expression and PUFA metabolism in the germ cells is low, a lipid transport from the Sertoli cells to the germ cells has been hypothesised. Phospholipids (PL) is the dominating lipid class in germ cells, while in Sertoli cells the triacylglycerols content equals that of PL. Furthermore, both in rat and human germ cells, phosphatidyl choline, phosphatidyl ethanolamine and phosphatidyl serine constitutes more than 80% of the PL. Uniquely for the mammalian spermatozoa, more than 50% of the PC fraction is actually choline plasmalogen, almost exclusively with 22:6(n-3) or 22:5(n-6) in the sn-2 position. After spermiation the spermatozoon has little capacity to alter its membrane. Thus, the sperm membrane changes taking place in the epididymis and female genital tract are mediated by modification or reorganisation of the cell surface by the surrounding environment. During sperm maturation in the epididymis, the anterior head membrane undergoes a well-defined series of chemical changes. These include an enrichment of highly unsaturated PL, which leads to a decrease in general membrane stability. Studies on ram sperm membrane indicate an increase in the total content of 22:6(n-3) from 14% to 25%. At the same time, addition of cholesterol (2 increase in the C:PL ratio) and an actively maintained asymmetric transmembrane PL distribution modulate this effect, stabilising the membrane of the mature sperm for storage. During capacitation the sperm is depleted in cholesterol, a process activated by HCO3-, and the membrane asymmetry is reset. After capacitation, seminolipid (SL), a specific sulphoglycolipid found only in mammalian sperm and Swann cells, migrates from the apical to the equatorial head membrane. SL interacts with a sulphoglycolipid immobilizing protein (SLIP-1) which binds to the oolemma. This orients the sperm in a lateral fashion. Activated SLIP-1 desulphates SL. Due to its relative small head group, desulphated SL can now induce inverted micelles that facilitate fusion. With the formation of the diploid zygote, the sperm membrane has fulfilled its obligations, and the spermatozoon terminates its lifespan.

• Sæther, Thomas; Tran, Thien Ngoc; Christophersen, Bjørn & Haugen, Trine Berit (2002). Effect of Dietary Fats, Insulin and Dexamethasone on delta6-desaturase Expression in Rat Testis. Full text in Research Archive Show summary

  The testis is an extraordinary organ regarding the fatty acid metabolism. Although rich in polyunsaturated fatty acids (PUFAs), the testis is continuously drained of these fatty acids, as the spermatozoa are transferred to the epididymis. This makes a great contrast to other PUFA-rich tissues like the brain and retina. In all cells the dietary essential fatty acids; linoleic acid (18:2(n-6)) and linolenic acid (18:3(n-3)) are converted to the important fatty acids 22:5(n-6) and 22:6(n-3) by alternating steps of elongation and desaturation. The delta6-desaturase catalyses a rate-limiting step in this conversion. Germ cells are especially rich in PUFAs, more than the Sertoli cells, but Sertoli cells seem to be more active in converting the dietary essential fatty acids to 22:5(n-6) and 22:6(n-3), than germ cells are. We have recently showed that delta6-desaturase is regulated differently in the testis that in liver in response to essential fatty acid deficiency (EFAD), induced by a fat free diet. In liver delta6-desaturase expression is upregulated in response to EFAD, while in testis no such increase is observed. This may be explained by differences in the expression pattern of the PPARs (peroxisome proliferating activated receptors) in liver and testis, a nuclear receptor family governing the fatty acid metabolism. Both dexamethasone and insulin induce an upregulation of the delta6-desaturase expression in the Sertoli cells. The induction is more rapid with dexamethasone than with insulin. When stimulating Sertoli cell cultures with arachidonic acid in combination with dexamethasone and insulin respectivly, only a very small drop in delta6-desaturase expression is observed. Arachidonic acid is known to bind to PPAR-alpha as a ligand, and in tissues like the liver, induce a marked downregulation of the delta6-desaturase expression. This difference in response to arachidonic acid can partly explain the results seen in the feeding experiment.

• Malm, Gunilla; Haugen, Trine Berit; Henrichsen, Trine; Bjørsvik, Cathrine; Grotmol, Tom & Sæther, Thomas [Show all 10 contributors for this article] (2002). No Seasonal Variation in Sperm Parameters despite Extreme Differences in Daylight Conditions North of the Arctic Circle. Full text in Research Archive
• Sæther, Thomas; Tran, Thien Ngoc; Christophersen, Bjørn & Haugen, Trine Berit (2002). Effect of Dietary Fats, Insulin and Dexamethasone on delta6-desaturase Expression in Rat Testis. Full text in Research Archive
• Sæther, Thomas; Tran, Thien Ngoc; Christophersen, Bjørn & Haugen, Trine Berit (2001). Effect of Dietary Fats, Insulin and Dexamethasone on delta6-desaturase Expression in Rat Testis. Full text in Research Archive
• Tran, Thien Ngoc; Sæther, Thomas; Christophersen, Bjørn; Rootwelt, Helge; Retterstøl, Kjetil & Haugen, Trine Berit (2001). Expression of delta6- and delta5-desaturase in Rat Testis. Full text in Research Archive Show summary

  Previous studies have shown that rat fed diets deficient in essential fatty acids show testicular atrophy and become infertile. This was not prevented by the inclusion of linolenic acid (18:3n-3), but the testicular development was normal when the diet was supplemented with linoleic acid (18:2n-6). In most animal cells 22:6(n-3) is the major 22-carbon polyunsaturated fatty acid in the membrane lipids, whereas rat testis contains more 22:5(n-6) than 22:6(n-3). The amount of 22:5(n-6) increases from 2 to 20% of total fatty acids in the progression of germ cell differentiation from spermatogonia to condensing spermatids, and this level is higher than in Sertoli cells. The linolenic acid and linoleic acid are converted to 22:6(n-3) and 22:5(n-6) by alternating sequences of elongation and desaturation. The delta6-desaturase catalyzes a rate-limiting step in the conversion of 18:3(n-3) and18:2(n-6) to 18:4(n-3) and 18:3(n-6), respectively, whereas the rate of desaturation of 20:4(n-3) and 20:3(n-6) is determined by the activity of delta5-desaturase. This study demonstrates the expression of both delta5- and delta6-desaturase mRNA in rat testis. The levels of the transcripts were high in Sertoli cells, whereas only weak signals were observed in the germ cell fractions. The results are consistent with previous report that Sertoli cells were more active to convert 18:2(n-6) and 20:4(n-6) to 22:5(n-6) than germ cells and support the hypothesis that biosynthesized C22:5(n-6) from Sertoli cells can be transferred to developing germ cells. Furthermore, our results suggest that the regulation of the desaturases is different in liver and testis.

• Sæther, Thomas; Aspelund, Trond; Eie, Knut; Hobøl, Erling; Ingvaldsen, Christoffer Aam & Starholm, Trude (2018). NØFs vannfugltellinger i Nordre Øyeren - kortrapport 2018 og regresjonsanalyser i forbindelse med flomtappingsprosjektet. Nordre Øyeren fuglestasjon. Full text in Research Archive
• Sæther, Thomas; Aspelund, Trond; Eie, Knut; Hobøl, Erling; Ingvaldsen, Christoffer Aam & Starholm, Trude (2018). Sluttrapport fra vaderregistreringer på Årnestangen 2015-2018. Nordre Øyeren fuglestasjon. Full text in Research Archive Show summary

  Nordre Øyeren naturreservat er et av Norges viktigste rasteområder for vann‐ og vadefugl under trekket, både vår og høst. Her stopper fuglene for å spise og hvile før de flyr videre. Endringen i vannstanden gjennom året, og fra år til år, er den enkeltfaktoren som betyr mest for den vanntilknyttede delen av fuglefaunaen i Øyeren. I dag er det regulanten, Glommen og Laagens brukseierforening (GLB) som regulerer vannstanden gjennom konsesjonen gitt av Olje‐ og energidepartementet og Norges vassdrags‐ og energidirektorat (OED/NVE). Sommeren 2014 startet GLB opp et 5‐årig prøveprosjekt med justert flomreglement for Øyeren, der regulanten hadde fått tillatelse til å øke tappingen av Øyeren i forhold til gjeldende flomtappekurve fra juni til september. Bakgrunnen for og målsettingen med denne prøveperioden var å innhente tilstrekkelig kunnskap om effektene av økt flomtapping på erosjonsforhold og om ulemper for brukerinteressene i Nordre Øyeren. Nordre Øyeren fuglestasjon fikk i oppdrag å undersøke vannstandens effekt på vadertrekket. Gjennom fire høstsesonger (2015‐2018) og 40 feltdager ble vadertrekket på tuppen av Årnestangen registrert. Sammenhengen mellom antall individer, arter, vannstand og dato ble modellert og multiple lineære regresjonsanalyser utført ved hjelp av analysepakken ggplot i R. Disse analysene viste en signifikant negativ sammenheng mellom 1) vannstand og antall vadere, 2) vannstand og antall arter, og 3) vannstand og vaderstørrelse. Det er de minste vaderne i slektene Calidris og Charadrius som er mest utsatt når vannstanden øker. Dette skyldes sannsynligvis at muligheten for fødesøk forsvinner. Bare en lokal vannstand under 4,90 meter muliggjør et akseptabelt artsmangfold og dagantall av vadere under høsttrekket gjennom Nordre Øyeren naturreservat. De største antallene av vadere i Øyeren observeres på vannstander under 4,60 meter lokal høyde på våren. Det er grunn til å tro at tilsvarende vannstander ville kunne gitt rastemuligheter for betydelig flere vadere i Nordre Øyeren også på høsten. En forsert flomtapping som sikter mot å redusere antall og lengden av episoder med vannstand over 5,00 meter i Øyeren, vil øke sannsynligheten for dager med forhold som er gunstige for vadere. Dette er viktig for en gruppe av fugler der flere av artene er truet og befinner seg på den norske rødlista.

• Sæther, Thomas & Erling, Hobøl (2010). Hekkefugltaksering på Fautøya og Rossholmens vesttange, Sesongrapport 2010. Nordre Øyeren fuglestasjon. Full text in Research Archive
• Kvebæk, Yngve; Sæther, Thomas; Aspelund, Trond & Hobøl, Erling (2009). NORDRE ØYEREN - Trend, trekkprofil og preferanseområde for viktige vannfuglarter - Komplett statusliste og øvrige artsvurderinger. Fylkesmannen i Oslo og Akershus. Full text in Research Archive Show summary

  Trendanalyser er utført for en rekke vannfuglarter i Nordre Øyeren for perioden 1976–2008 og bygger på Nordre Øyeren Fuglestasjons omfangsrike grunnlagsmateriale. For et flertall av artene ble det observert en økende trend for bruk av reservatet. Dette gjenspeiler den regionale utviklingen for flere av artene, men enkelte unntak kan sees. Sangsvane og stokkand er to slike eksempler som diskuteres nærmere. Det digitale materialet er også gjennomgått for å påvise de samme artenes preferanse for ulike soner i området. Det framgår av analysen at Snekkervika og området sør for vika, de sentrale vannarealer i sør, Rossholmen-området, arealet sør for Tuentangen og Svellets østlige del har tyngd en av vannfuglene. Det er dessuten gjort et forsøk på en mer presis lokalisering for gressendenes del ved hjelp av kartmaterialet fra tellingene. Denne tilnærmingen spisser preferansene ytterligere og gir en mer presis lokalisering. Enkelte øvrige arter er gitt en vurdering med tanke på forekomst før og nå. Det er utarbeidet en oppdatert statusliste med sesong- og hekke forekomst i tillegg til en konsentrert vurdering. Listen omfatter arter registrert i Nordre Øyeren Fuglestasjons observasjonsområde som her går under betegnelsen Nordre Øyeren. Det inkluderer Sørumsneset og Nordre Øyeren naturreservater med nærmeste omegn. Totalt er det pr. 31.12.2008 registrert 268 fuglearter i dette området. I tillegg er det laget en ajourført artsliste spesifikt for Sørumsneset naturreservat og som i dag teller 137 arter.

• Sæther, Thomas (2008). Positive and negative modulation of the transactivation potential of the transcription factor c-Myb : novel regulatory mechanisms for a classical proto-oncoprotein. Universitetet i Oslo. Full text in Research Archive
• Sæther, Thomas & Haugen, Trine B. (2003). Metabolism of polyunsaturated fatty acids in rat testis. Universitetet i Oslo. Full text in Research Archive
• Sæther, Thomas (2003). Metabolism of Polyunsaturated Fatty Acid in Rat Testis : Expression and regulation of delta5-desaturase, delta6-desaturase, stearoyl-CoA desaturase 1, stearoyl-CoA desaturase 2 and the nuclear receptors peroxisome proliferator-activated receptor alpha, delta and gamma. Universitetet i Oslo. Full text in Research Archive Show summary

  In mammalian cells essential polyunsaturated fatty acids (PUFAs) are converted to longer PUFAs by alternating steps of elongation and desaturation. In contrast to other PUFA-rich tissues, the testis is continuously drained of these fatty acids, as spermatozoa are transported to the epididymis. Alteration of the germ cell lipid profile from spermatogonia to condensing spermatids and mature spermatozoa had been described prior to this work, but the male gonadal gene expression of the desaturases, responsible for the PUFA-metabolism, was still not established. The focus of this study was to characterise the expression and regulation of stearoyl-Coenzyme A (CoA) desaturase 1 (SCD1), stearoyl-CoA desaturase 2 (SCD2), delta5- and delta6-desaturase in rat testis. Desaturase gene expression was detected in testis, epididymis and fractionated cells from seminiferous tubulus using Northern blot analysis. For the first time SCD1 and SCD2 expression are demonstrated in rat testis and epididymis. Both SCDs are expressed in epididymis, while testis mainly contains SCD2. Examination of the testicular distribution of delta5- and delta6-desaturase and SCD1 and -2 shows that all four desaturases seem to be localised in the Sertoli cells, with far lower expression in germ cells. In light of earlier published results showing that germ cells are richer in PUFAs than Sertoli cells, this strengthens the hypothesis of a lipid transport from the Sertoli cells to the germ cells. As opposed to what is shown in liver, delta5- and delta6-desaturase mRNA levels in Sertoli cells are upregulated by dexamethasone. Furthermore, dexamethasone induces SCD2 mRNA. Insulin also upregulates these three genes in the Sertoli cell, while SCD1 mRNA is downregulated by both insulin and dexamethasone. Delta5- and delta6-desaturase, SCD1 and SCD2 are all upregulated by follicle-stimulating hormone (FSH). A similar upregulation of the desaturases is observed when treating Sertoli cells with (Bu)2cAMP, indicating that the desaturase upregulation observed with FSH treatment results from elevated levels of cAMP. Testosterone has no influence on the desaturase gene expression, at age 19 days. Thus, FSH seems to be a key regulator of the desaturase expression in the Sertoli cell. Neither SCD1 or -2, nor delta5- and delta6-desaturase are upregulated in whole testis tissue in response to two weeks feeding of a fat free diet. This makes a great contrast to what is seen in liver and kidney. Both in liver and kidney SCD1 and delta5- and delta6-desaturase are upregulated, accompanied by increased levels of fatty acids in the n-9 family. In liver the Mead acid (20:3(n-9)) to arachidonic acid (20:4(n-6)) ratio reached 0,75. Also in testis increased n-9 levels are seen; 20:3(n-9)/20:4(n-6)=0,36. However, this is probably resulting from decreased supply of n-3 and n-6 substrates. At present we hypothesise that the desaturases in testis are insensitive to essential fatty acid deficiency (EFAD), and furthermore, that the vacant desaturase response is due to differences on the transcription factor level. The low testicular responsiveness to changes in the PUFA pool is confirmed as Sertoli cells treated with arachidonic or tetradecylthioacetic (TTA) acid only show a weak to non-excising downregulation of the desaturases (less than 1,5-fold). The downregulation of the desaturases in response to PUFAs in hepatocytes has been reported to be more than 4-fold. However, the fact that the net effect of TTA, a strong PPAR-alpha agonist, is desaturase-repressive, indicates that some nuclear mediator of desaturase repression must be present in low doses, also in testis. Peroxisome proliferator-activated receptor (PPAR) alpha, delta and gamma are expressed in rat testis, with PPAR-alphaƒnshowing a gene expression pattern quite similar to delta5- and delta6-desaturase, as the Sertoli cell is the cell type with the highest expression. Furthermore, PPAR-gamma expression also dominates in the Sertoli cells. PPAR-delta expression is for the first time demonstrated in rat germ cells, with high levels in round spermatids. PPAR-alpha and -gamma are known to control numerous genes related to lipid metabolism including PUFA desaturation. Hence, the co-localisation of the desaturases and e.g. PPAR-alpha can not be coincidental. Since PPAR-alpha expression in the Sertoli cells has been proven to be stage specific, and regulated by FSH, the induction of the desaturases in response to FSH reported here, could be resulting from a combined primary FSH-cAMP-CREB action and secondary FSH-PPAR-alpha-ligand action. Finally, we show that PPAR-alpha is slightly downregulated in testis in response to the fat free diet, while upregulated in liver and kidney. Acknowledging that PPAR-alpha induces delta5- and delta6-desaturase, and that the same genes are upregulated in the EFAD liver and kidney, we speculate if the increased level of PPAR-alpha mRNA adds to the SREBP-1c-governed induction of delta5- and delta6-desaturase under EFAD conditions in these tissues. Furthermore, the small downregulation of PPAR-alpha in the EFAD testis could explain how an abolished desaturase repression seen in PUFA-treated Sertoli cells, would disappear in whole testis tissue from fat free diet-fed rats.

View all works in NVA