The group is involved in several projects.
Identification of transcriptional factors regulating expression of lipid droplet binding proteins (Plin genes).
The Plin gene family consists of five Plin genes (Plin1-5). These are tissue-specifically expressed and encode for proteins that bind to the surface of lipid droplets (LDs). The LD-group has characterized the promoters of all Plin genes and mapped PPAR responsive elements in the Plin1, Plin2, Plin4 and Plin5 genes. This work has helped to understand the tissue-specific and hormonal responsive expression pattern of the Plin genes.
Lipid droplets in the heart
Ischemic heart disease is currently a leading cause of immediate death worldwide. Studies suggest that manipulation of cardiac energy metabolism can be used to improve the outcome of acute myocardial ischemia. The fuel preference by the heart is influenced by various physiological and pathophysiological conditions. Normally, the working heart will consume mixed energy substrates to produce ATP where 60%-70% of the cardiac ATP will be generated from oxidation of fatty acids. Cardiac cells, such as cardiomyocytes, store a limited reservoir of fatty acids in the form of triacylglycerol (TAG) in lipid droplets (LDs).
Under pathological conditions, e.g. obesity, diabetes mellitus and myocardial ischemia, increased lipid accumulation is often observed in the heart. The role of such cardiac LD storage for the outcome of ischemic disease is currently not clear. In this project, various Plin null models are being characterized in collaboration with Malin Levin at Sahlgrenska Academy at University of Gothenburg and Kåre-Olav Stensløkken at the institute.
Lipid droplets, insulin resistance and type 2 diabetes
At a molecular level, the main difference between normal weighted and obese individuals is the massive increased accumulation of excess lipids within lipid droplet (LD) organelles in multiple organs, such as liver, muscle and pancreas. Such accumulation is a strong predictor for various types of clinical complications - including insulin resistance and type 2 diabetes mellitus (T2D). Strategies to reduce the risk of development of T2D in obese include dietary advice toward a healthier diet combined with various medications. Various approaches are used to treat T2D, but all targets broadly with a secondary improvement of insulin sensitivity. Despite intense research for decades, obesity and associated complications are amongst the strongest determinants for reduced life expectancy and development of chronic diseases in the Norwegian population. Researching less explored molecular pathways, to discover and develop drugs to target alternative molecular pathways, must have high priority to reduce future health costs linked to obesity.
A strong association between accumulation of LD organelles and lipid-mediated diseases is well known. In fact, LD often serve as pathological markers for the lipid diseases in question. Still, the contribution of accumulated LD organelles for disease development is poorly understood. The project combines metabolic phenotyping of genetically modified mouse models with defective lipid droplet storage (Plin null mice) with state of the art molecular techniques carefully selected to investigate the influence of the LD organelle on organ metabolism and function. A number of parallel projects are currently ongoing related to various Plin null mice generated by Dalen at National Institutes of Health (NIH) in 2005-2009. The work carried out in Norway is coordinated by associate Professor Knut Tomas Dalen, in collaboration with Prof. Alan R. Kimmel at NIDDK, NIH, US.