Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Obesity and metabolic syndrome-associated insulin resistance, which affects more than one third of adults in the US, causes increased lipogenesis, hypertriglyceridemia and a greater than 2-fold increase in the risk of CVD. However, the molecules and mechanisms by which insulin resistance increases CVD are not clear. Liver X receptor (LXR) is a nuclear receptor which plays a central role in control of both lipid and cholesterol metabolism. LXR is presumably activated in the hyperinsulinemic, obese liver since the lipogenic targets of LXR, such as sterol response element binding protein 1c (SREBP1c), the master lipogenic transcriptional factor, are constitutively activated in a LXR-dependent manner. However, LXR cholesterol efflux targets, such as the ATP binding cassette transporters, ACBG5 and ABCG8, are not induced in insulin resistant states. Thus, we hypothesize that insulin selectively activates the ability of LXR to induce transcription of its lipogenic targets and that this regulation remains active in insulin resistant state. The objective of this proposal are to determine how insulin regulates LXR, how this regulation is changed in insulin resistant states and the contribution of LXR to the changes in lipogenic and cholesterol efflux gene expression observed in insulin resistant states. Thus we propose to first identify the signaling pathways and mechanisms by which insulin activates LXR in the K99 phase. With such knowledge we will then determine how insulin resistance differentially modifies LXR activity in the regulation of lipogenesis and cholesterol efflux genes in the R00 phase. It is our expectation that the results of our proposed studies will provide important insights into the transcriptional control of lipid and cholesterol metabolism in the insulin resistant state and potentially provide a novel mechanism by which insulin resistance promotes CVD. Moreover, by understanding how transcription of the lipogenic and cholesterol efflux targets can be dissociated, we may be able to develop novel therapies to selectively activate the cholesterol efflux targets via LXR, without activating lipogenesis.
The overall goal of this proposal is to determine how insulin activates Liver X Receptor and the contribution of Liver X Receptor to the changes in lipogenic and cholesterol efflux gene expression in insulin resistant states. It is our expectation that the results of our proposed studies will provide important insights into the transcriptional control of lipid and cholesterol metabolism in the insulin resistant state.
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