This Program Project Grant (PPG) began 40 years ago when two of us (Brown and Goldstein) delineated the LDL receptor pathway for control of cholesterol metabolism and showed how genetic defects in the receptor produce Familial Hypercholesterolemia and atherosclerosis. Over the ensuing years, our goals broadened and the number of investigators increased, but the focus of this PPG remains the same, namely, that many diseases result from misregulation of metabolism and that understanding the molecular basis for regulation of lipid metabolism will lead to prevention and therapy of common lipid-related disorders, including atherosclerosis and the complications of diabetes. In recent years, our PPG team has continued to produce high quality and unexpected results that have opened new fields of investigation, two of which include: 1) discovery of the SREBP pathway as a master regulator of lipid synthesis and LDL clearance, with implications for diseases ranging from atherosclerosis to fatty liver disease; 2) discovery of the LDL-lowering action of PCSK9 and how loss-of-function mutations in PCSK9 produce life-long reductions in plasma LDL and almost complete protection against coronary artery disease – a discovery that stimulated development of two FDA-approved anti-PCSK9 monoclonal antibodies for treatment of severe hypercholesterolemia. In addition to these discoveries, the team supported by this PPG has generated more than 400 unique cDNA clones, monoclonal antibodies, mutant cell lines, and genetically engineered mice, all of which are provided to the scientific community with “no strings attached.” We now apply for a 5-year renewal (Years 41-45) to probe more deeply into the biochemistry and physiology of several proteins whose regulatory actions are central to lipid metabolism and human disease – SREBPs and their regulators, Scap and Insigs; HMG-CoA reductase and two of its regulators, UBIAD1 and PPD1; ACCs (acetyl-CoA carboxylases), key enzymes in fatty acid synthesis; UBXD8, a regulator of unsaturated fatty acids; and ANGPTL3 and ANGPTL8, two regulators of triglyceride clearance. We will explore the regulatory actions of these proteins through integrated interdisciplinary approaches covering the whole range of biology, including genes, mRNAs, cells, experimental animals, and human subjects. If the past predicts the future, we will continue to make discoveries that have direct implications for human health. C/PPG 2015 – Overall - Project Summary