Characterization of Novel Insulin Regulated Pathways in Fat Synthesis in Liver and Adipose Tissue

Diets rich in lipids and carbohydrates together with a lack of physical exercise predispose individuals to multifunctional diseases such as atherosclerosis, hyperlipidemia, obesity, insulin resistance and diabetes type 2. Fat metabolism and glucose homeos tasis are inherently related, and insulin is probably the most important hormonal factor influencing their intimate link. The important role of insulin is to maintain the blood glucose concentration within a narrow range. The effects of insulin on express ion of lipogenic genes are mediated by the transcription factor sterol regulatory element-binding protein-1c (SREBP-1c). SREBP-1c can be induced by activation of liver X receptors (LXRs), which belong to a group of ligand-activated transcription factors c alled nuclear receptors. They are recognized as important intracellular signal transmitters of nutritional and pharmacological compounds. Recent findings in our group support a key role of LXRs in lipogenesis, demonstrating that LXRs are insulin mediating factors in liver. Although it is clear that both LXR and insulin are necessarily and crucial for controlling lipid and glucose metabolism, the molecular mechanisms responsible for this regulation are highly unknown. Interestingly, by screening studies we have recently identified a group of proteins (Foxo) as possible interaction-partners for LXRs. These proteins are specifically interesting in relation to lipogenesis because they function as sensors of the insulin signaling pathway. This project aims at understanding the contribution of the nutritional and pharmacological controlled LXRs in fat synthesis. The objectives will be to study the nutritional and pharmacological regulation of LXRs, characterize novel insulin regulated pathways through LXR and Foxo proteins, investigate mechanism controlling tissue-specific regulation of lipid metabolism, and to reveal the inherently relation of total fat metabolism and glucose homeostasis.