This Program Project Grant (PPG) began 35 years ago when we delineated the LDL receptor pathway for control of cholesterol metabolism and showed that defects in the LDL receptor produce Familial Hypercholesterolemia and atherosclerosis. After 35 years, our goals have broadened and the participants have increased, but the focus remains the same: to understand the genetic and molecular basis for regulation of lipid and lipoprotein metabolism and to use this knowledge to prevent and treat lipid-related diseases i.e., atherosclerosis and Metabolic Syndrome. During the last 5 years, we published 164 papers, reporting the following major advances: 1) discovery of Scap as the sensing receptor for membrane cholesterol that controls SREBP processing, thereby determining LDL receptor number and plasma LDL level;2) discovery of mutations in PCSK9 that lower plasma LDL and decrease heart attacks as much as 88%;3) demonstration that PCSK9 functions extracellularly to bind and degrade LDL receptors, an observation that stimulated pharmaceutical companies to develop antibodies that block PCSK9 and lower LDL;4) elucidation of the hydrophobic handoff mechanism for export of LDL-derived cholesterol from lysosomes;5) delineation of the sterol-regulated, ubiquitin-mediated pathway for degradation of HMG CoA reductase and lnsig-1;6) discovery of GOAT, the enzyme that attaches octanoic acid to ghrelin, a covalent modification required for ghrelin's activity in controlling appetite and blod sugar;7) identification of a protein, MIG12, that activates fatty acid synthesis in liver;8) discovery of 25-hydroxycholesterol as an immunoregulatory sterol that links the innate and adaptive immune systems;and 9) elucidation of an LRP1- mediated signaling pathway that protects vascular smooth muscle cells against atherosclerosis. We now apply for a 5-year renewal (Years 36-40) to further study these and related phenomena through an integrated, multidisciplinary approach. We propose to learn more about known molecules and to discover new ones that regulate lipid and lipoprotein metabolism as it relates to disease. We will continue to study these processes at all levels - molecules (i.e., gene, mRNA, protein), cells, experimental animals, and human patients. We will employ multiple approaches - biochemistry, molecular biology, genetics, cell biology, gene-manipulated mice, animal physiology, clinical genetics, and genomics. Such an integrated interdisciplinary approach is possible only through continued support of this PPG.

Public Health Relevance

Disordered fat metabolism lies at the root of two common and devastating diseases in industrialized societies: cardiovascular disease and diabetes. Deep understanding of cholesterol metabolism, much of which resulted from this PPG, has already reduced coronary disease. Further reductions in vascular disease will follow from future advances resulting from studies proposed in this PPG renewal. We have already provided an unprecedented number of novel research tools (>380 different cDNA clones, cell lines, monoclonal and polyclonal antibodies, specialized plasmid constructs, transgenic and knockout mice) to the scientific communitv. and many more will emerge from this renewal.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL020948-36A1
Application #
8266654
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Liu, Lijuan
Project Start
1997-07-15
Project End
2017-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
36
Fiscal Year
2012
Total Cost
$4,280,700
Indirect Cost
$1,587,024
Name
University of Texas Sw Medical Center Dallas
Department
Genetics
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Liu, Jingjing; Moon, Young-Ah (2016) Simple Purification of Adeno-Associated Virus-DJ for Liver-Specific Gene Expression. Yonsei Med J 57:790-4
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
Hwang, Seonghwan; Hartman, Isamu Z; Calhoun, Leona N et al. (2016) Contribution of Accelerated Degradation to Feedback Regulation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Cholesterol Metabolism in the Liver. J Biol Chem 291:13479-94
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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