Hormonal regulation of LDL receptor trafficking

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This proposal will elucidate the function of the exocyst complex and actin dynamics in lipoprotein metabolism and its regulation by insulin. Our preliminary data reveal that insulin stimulates the recycling of the LDL Receptor in hepatocytes to increase the delivery of LPL into cells. We hypothesize that insulin controls the activity of the small GTPase RalA in hepatocytes by two pathways involving phosphorylation and inhibition of its GAP protein, and recruitment of its GEF protein. Once activated, RalA can interact with components of the targeting exocyst complex, resulting in the tethering of exocytotic vesicles containing the LDLR at discrete regions of the basolateral plasma membrane that are enriched in machinery required for fusion. We also hypothesize that insulin regulates the dynamics of cortical actin to propel LDLR endocytosis. We will evaluate: i) the role of the exocyst complex, and its regulators RalGAP, RalGEFs and RalA in the regulation of polarized LDLR exocytosis in hepatocytes; ii) the role of changes in the cortical actin cytoskeleton in governing LDLR endocytosis; iii) the physiological relevance of these hepatic signaling and trafficking events to overall lipoprotein metabolism. These new ideas and approaches will elucidate the key elements in control of these trafficking itineraries, and may ultimately generate valuable insights into the molecular mechanisms underlying dyslipidemia in obesity and Type 2 diabetes.