Sex/Gender Difference Supplement: The role of hepatic insulin resistance on SR-BI dependent HDL cholesterol uptake

  • Graf, Gregory (PI)
  • Thatcher, Sean (CoI)
  • Van Der Westhuyzen, Deneys (CoI)

Grants and Contracts Details


The overall objective of this proposal is to examine the extent to which impaired insulin signaling alters HDL-mediated reverse cholesterol transport (RCT). A key cardioprotective function of HDL is the delivery of excess cholesterol from plasma and tissues to the liver for elimination from the body via RCT. SR-BI is the major hepatic HDL receptor and mediates the selective uptake of HDL cholesterol esters (HDL-CE). Compared to other circulating lipoproteins, cholesterol carried on HDL particles is preferentially secreted into bile in an SR-BI dependent manner. In addition to SR-BI’s role in trans-hepatic sterol transport, both gain and loss-of-function studies have established that SR-BI is a determinant of hepatic cholesterol metabolism including cholesterol synthesis, biliary cholesterol excretion rates and the incorporation of cholesterol into VLDL. Both HDLCE uptake and biliary cholesterol secretion have been shown to be negatively affected by impaired insulin signaling, a key contributing element to the Metabolic Syndrome (MetS) and the increased risk for cardiovascular disease. Our published and preliminary data indicate that insulin signaling regulates SR-BI by a novel post-translational mechanism that promotes SR-BI expression on the plasma membrane. We hypothesize that insulin resistance reduces HDL-CE uptake and alters SR-BIdependent delivery of cholesterol to hepatic regulatory and secretory pools through mechanisms that include the redistribution of SR-BI to an intracellular compartment. Specific Aim 1 will determine the effect of hepatic insulin signaling and insulin resistance on SR-BI mediated sterol trafficking to secretory and regulatory hepatic cholesterol pools. Hepatic insulin signaling will be disrupted by selective depletion of insulin receptors or by expression of a dominant negative phosphatidylinositol-3 kinase (AdnilPI3K) and the extent to which hepatic insulin resistance reduces SR-BI mediated HDL-C selective cholesterol ester uptake determined. Studies will also determine how reduced SR-BI function alters steady-state hepatic cholesterol synthesis and secretion in the setting of impaired insulin signaling? Specific Aim 2 will test the hypothesis that transhepatic (THCE) elimination of HDL cholesterol in bile is reduced in the setting of hepatic insulin resistance and hypertriglyceridemia. This will be accomplished by a) determining whether reduced SR-BI function diminishes THCE of HDL-C, b) determining whether hepatic IR decreases macrophage to feces RCT in an SR-BI dependent manner, and c) examining whether changes in HDL particle composition disrupt THCE of HDL-C and synergize with SR-BI dysfunction to reduce HDL RCT function. Specific Aim 3 will determine the molecular mechanisms by which insulin signaling regulates SR-BI cell surface localization in hepatocytes. The effect of insulindependent PI3K signaling on SR-BI subcellular distribution will be examined in cultured hepatocytes, together with the identity of the intracellular compartment(s) in which SR-BI accumulates as a result of impaired insulin signaling. The responsible insulin-dependent signaling pathways will be defined and studies will be performed to identify the determinants on SR-BI necessary for its regulation by insulin signaling. Rationale for Administrative Supplement: In the course of conducting this project, we have observed substantial and unexpected sexually dimorphic phenotypes related to cholesterol elimination and reverse cholesterol transport (see preliminary data). This supplement will allow us to 1) further characterize the phenotype and 2) conduct mechanistic studies that address the role of sex steroids in the regulation of cholesterol elimination. The completion of these studies will result in the opening of a new area of investigation in cholesterol metabolism and its impact on the development of cardiometabolic disease. Specific Aim of Research Supplement: Determine the impact of sex steroids on the expression of the ABCG5 ABCG8 (G5G8) sterol transporter, the relative rates of biliary and intestinal cholesterol secretion, and the route of cholesterol elimination from plasma lipoproteins.
Effective start/end date9/20/138/31/18


  • National Institute Diabetes & Digestive & Kidney


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