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)
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
Budget End
Support Year
38
Fiscal Year
2014
Total Cost
Indirect Cost
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Smagris, Eriks; Gilyard, Shenise; BasuRay, Soumik et al. (2016) Inactivation of Tm6sf2, a Gene Defective in Fatty Liver Disease, Impairs Lipidation but Not Secretion of Very Low Density Lipoproteins. J Biol Chem 291:10659-76
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Schumacher, Marc M; Jun, Dong-Jae; Jo, Youngah et al. (2016) Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi. J Lipid Res 57:1286-99
Tian, Jing; Goldstein, Joseph L; Brown, Michael S (2016) Insulin induction of SREBP-1c in rodent liver requires LXRα-C/EBPβ complex. Proc Natl Acad Sci U S A 113:8182-7
Theodoropoulos, Panayotis C; Gonzales, Stephen S; Winterton, Sarah E et al. (2016) Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase. Nat Chem Biol 12:218-25
Bartuzi, Paulina; Billadeau, Daniel D; Favier, Robert et al. (2016) CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL. Nat Commun 7:10961
Lee, Jyh-Yeuan; Kinch, Lisa N; Borek, Dominika M et al. (2016) Crystal structure of the human sterol transporter ABCG5/ABCG8. Nature 533:561-4
Chen, Qiuyue; Denard, Bray; Lee, Ching-En et al. (2016) Inverting the Topology of a Transmembrane Protein by Regulating the Translocation of the First Transmembrane Helix. Mol Cell 63:567-78
Zhang, Yinxin; Lee, Kwang Min; Kinch, Lisa N et al. (2016) Direct Demonstration That Loop1 of Scap Binds to Loop7: A CRUCIAL EVENT IN CHOLESTEROL HOMEOSTASIS. J Biol Chem 291:12888-96

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