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 homeostasis 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 expression 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 called
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. Lately, glucose has additionally been suggested to play a role in LXR regulation of fat synthesis. Although glucose was suggested to be a ligand for LXR, this has been hardly debated. Our latest data reveal another mechanism for glucose to regulate the activity of the LXR proteins, namely through modification of both LXRalfa and LXRbeta (Anthonisen et al., JBC 2010).
This project aims at understanding the contribution of the nutritional and pharmacological controlled LXRs in fat synthesis. The objectives are to study the nutritional and pharmacological regulation of LXRs, characterize novel insulin regulated pathways through LXR, characterize regulation of LXR activity by insulin and glucose, investigate mechanism controlling tissue-specific regulation of lipid metabolism, and to reveal the inherently relation of total fat metabolism and glucose homeostasis.
