Nuclear receptors are ligand-activated transcription factors and important intracellular signal transmitters that function as nutritional sensors controlling lipid metabolism, glucose homeostasis, and inflammation.We have focused on the integrated molecular-to-organism view to elucidate the contribution of the nuclear receptors to the pathophysiology of metabolic disorders.
- LXRs are regulated by lipids (Tobin et al Mol. Endo, 2000) and are insulin mediators activating hepatic lipogenesis (Tobin et al JBC, 2002).
- Lack of LXRα protects against hepatic steatosis. Still LXRα KO mice are insulin resistant due to increased inflammation in liver. LXRβ KO mice are insulin sensitive with reduced insulin clearance capacity during clamp (Holm et al BBRC, 2010).
- LXRs play a role in lipid accumulation in adipose tissue (Juvet et al, Mol Endo, 2003. Ross et al. MCB, 2002).
- Identification of novel LXR target genes: Hepatic fatty acid elongase 5 (Elovl5), which primarily elongate C18-20 PUFAs (Qin et al BBA Lipids, 2009), long-chain acyl-CoA synthetase 3 (ACSL3) (Weedon-Fekjaer, JLR, 2010), GLUT4, glucose transporter in adipose tissue (Dalen, JBC, 2003) LXRa autoregulation in adipose tissue (J.Lipid.Research 2004).
- O-GlcNAcylation of LXR provides a novel mechanism for a direct nutritional regulation of lipid metabolism through control of LXR activity (Anthonisen et al JBC, 2010).
- Transcriptional regulation of the perilipin / Plin genes. Perilipins are amongst the most abundant proteins at the surface of lipid droplets, where they are believed to control the release of the stored content. We have characterized how these genes are regulated by distinct PPAR members in various tissues, and how the expression of these genes change in response to altered physiological stimuli (Dalen et al, BBA Lipids 2007, L Lipid Reserach 2006, J Biol Chem 2004).