The sterol regulatory element binding proteins (SREBPs) have been studied as key modulators of lipid metabolism but emerging data indicate they are involved in additional cellular pathways and processes. In mammals, there are three major SREBP isoforms encoded by two unlinked genes. The SREBP-1 gene has two isomers that only differ at their amino-terminal regions. The SREBP-2 gene encodes a single protein. SREBP-1 and 2 are regulated differently in the liver, SREBP-1c is activated by insulin signaling and is a major driver of the de novo lipogenesis program. SREBP-2 is activated by cholesterol depletion and is a major driver of cholesterol synthesis when hepatic sterol levels are low or subject to pharmacologic blockade by statin treatment. In a recent study, we described an SREBP regulated micro-RNA (miR) cluster that encodes three distinct miRs that are processed from a single SREBP regulated primary transcript. We went on to show that each miR negatively regulates expression of a different protein involved in the complex membrane-trafficking and proteolytic maturation pathway that controls the level of active nuclear SREBPs. This miR operon functions in a positive regulatory loop that increases SREBP activity. Studies in Aim 1 will enhance our understanding of this regulatory mechanism through genetic and pharmacologic manipulation in vivo. We explore another key signature feature of the SREBPs in Aim 2, which is they do not activate transcription efficiently alone and work in a concerted fashion with additional transcription factors that bind to adjacent DNA sites to stimulate target gene expression. This feature provides modular and dynamic flexibility for SREBPs and allows them to function in combinatorial regulatory processes to integrate lipid synthesis with other key cellular physiologic processes. Most of this work in the past has been focused on isolated gene-promoters taking advantage of cultured cells and in vitro approaches. In our preliminary studies, we performed genome- wide binding studies for both SREBP-2 and one of its key hepatic partner proteins, LRH-1, and in Aim 2 we propose to take advantage of these studies to exploit key genetic models and a robust feeding protocol to explore SREBP-LRH-1 action in vivo.
This proposal studies the molecular features for lipid regulation in a mammalian model system in vivo. These studies have direct clinical significance because we plan to evaluate responses of mouse models fed a diet supplemented with lovastatin plus ezetimibe (LE). Both of these drugs are currently used in humans for treatment of hyperlipidemia and in fact, a combination therapy using both drugs has been under clinical investigation over the past several years. Thus, our studies will help understand how the mammalian body adapts to ingestion of these commonly used drugs and will provide useful information on how to potentially monitor clinical effectiveness and alter therapy accordingly. This could have significant impact by identifying new targets for future pharmaceutical and nutritional intervention strategies to combat the effects of lipid metabolic disorders, especially or those in the population who are refractory to current therapeutic protocols.
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