Despite significant advances in preventive therapies, CHD remains the leading cause of death in the United States. An elevated level of plasma LDL-C is the single most important risk factor for the development of this disease (16), and LDL-lowering forms the cornerstone of CHD prevention. During the last decade, PCSK9 (proprotein convertase subtilisin/kexin type 9) has emerged as a potent regulator of LDLR levels in liver, and thus of plasma LDL-C concentrations (17). We have shown that haploinsufficiency of PCSK9 due to loss-of-function mutations (18) is associated with a 28% reduction in plasma levels of LDL-C and an 88% reduction in cardiovascular events (2). The most compelling evidence of the importance of PCSK9 in plasma LDL-C metabolism is the finding that individuals with no circulating PCSK9 have exceedingly low plasma levels of LDL-C (-15 mg/dL) (19). To date, no adverse clinical sequela has been found in humans lacking PCSK9. These observations, which were made during the last funding period of this grant, established that blocking the action of PCSK9 is a viable and potent target for the treatment of hypercholesterolemia and the reduction of cardiovascular risk. As such, a complete characterization of the molecular mechanisms by which PCSK9 functions to degrade LDLRs is paramount.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL020948-38
Application #
8686026
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
38
Fiscal Year
2014
Total Cost
Indirect Cost
City
Dallas
State
TX
Country
United States
Zip Code
75390
Stender, Stefan; Smagris, Eriks; Lauridsen, Bo K et al. (2018) Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride. Hepatology 67:2182-2195
Schumacher, Marc M; Jun, Dong-Jae; Johnson, Brittany M et al. (2018) UbiA prenyltransferase domain-containing protein-1 modulates HMG-CoA reductase degradation to coordinate synthesis of sterol and nonsterol isoprenoids. J Biol Chem 293:312-323
Mitsche, Matthew A; Hobbs, Helen H; Cohen, Jonathan C (2018) Patatin-like phospholipase domain-containing protein 3 promotes transfer of essential fatty acids from triglycerides to phospholipids in hepatic lipid droplets. J Biol Chem 293:6958-6968
Banfi, Serena; Gusarova, Viktoria; Gromada, Jesper et al. (2018) Increased thermogenesis by a noncanonical pathway in ANGPTL3/8-deficient mice. Proc Natl Acad Sci U S A 115:E1249-E1258
Fine, Michael; Schmiege, Philip; Li, Xiaochun (2018) Structural basis for PtdInsP2-mediated human TRPML1 regulation. Nat Commun 9:4192
Linden, Albert G; Li, Shili; Choi, Hwa Y et al. (2018) Interplay between ChREBP and SREBP-1c coordinates postprandial glycolysis and lipogenesis in livers of mice. J Lipid Res 59:475-487
Johnson, Brittany M; DeBose-Boyd, Russell A (2018) Underlying mechanisms for sterol-induced ubiquitination and ER-associated degradation of HMG CoA reductase. Semin Cell Dev Biol 81:121-128
Qi, Xiaofeng; Schmiege, Philip; Coutavas, Elias et al. (2018) Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex. Science 362:
Engelking, Luke J; Cantoria, Mary Jo; Xu, Yanchao et al. (2018) Developmental and extrahepatic physiological functions of SREBP pathway genes in mice. Semin Cell Dev Biol 81:98-109
Hobbs, Helen H (2018) Science, serendipity, and the single degree. J Clin Invest 128:4218-4223

Showing the most recent 10 out of 766 publications