Inter-organelle communication in lipid metabolism

PROJECT SUMMARY Atherosclerosis has presented an enormous burden to public health and economy with increasing prevalence. Cholesterol and triglyceride metabolism play crucial roles in atherogenesis. Genetic, epidemiologic, and clinical studies have revealed the causal role of LDL in atherosclerosis. The development of LDL-lowering drugs, including statins and those targeting PCSK9, has greatly improved the prevention and outcome of atherosclerosis. Despite advances in controlling LDL-C levels, a considerable residual risk remains for atherosclerotic cardiovascular diseases. In recent years, increasing evidence has linked triglyceride-rich lipoproteins (TGRLs), in particular VLDL, to atherosclerosis. The liver plays a central role in regulating triglyceride and cholesterol homeostasis. VLDL is synthesized in hepatocytes and secreted to the circulation. Their metabolism involves several steps: TG synthesis, lipoprotein particle assembly, intracellular trafficking from the ER to Golgi and secretion from Golgi. Although we have gained much knowledge about the whole process over the years, the regulatory mechanisms governing VLDL lipidation and transport from the ER to Golgi have not been fully understood. VLDL secretion is closely connected to lipid droplet (LD) metabolism. Excess lipids will be stored in LDs when lipid influx or synthesis surpasses VLDL secretion, while lipids in LDs can be delivered to apoB for VLDL biogenesis. However, the regulator mechanisms governing these interconnected processes remain elusive. Our preliminary data suggested that SEC16B, a scaffold protein located at the ER, mediates both VLDL and LD metabolism in the liver. The overall goal of this proposal is to define the roles of SEC16B in VLDL and LD metabolism using a series of in vitro and in vivo experiments. Aim 1 will examine how SEC16B regulates lipid droplets formation in hepatocytes. In Aim 2, we will elucidate the function and mechanisms of action of SEC16B in VLDL metabolism in the liver. The results of this work will define the novel functions of SEC16B in VLDL and LD metabolism, and provide insight whether SEC16B could be a novel therapeutic target for atherosclerosis.