The central theme of my research program is how dysregulation in the uptake and trafficking of dietary lipids contribute to human diseases, in particular coronary atherosclerosis and the metabolic syndrome. We identified the genes defective in two autosomal recessive forms of severe hypercholesterolemia, autosomal recessive hypercholesterolemia (ARH) and sitosterolemia, which are both associated with premature coronary artery disease (CHD). ARH is of interest because affected individuals have a tissue-specific disorder of LDL uptake. In normal individuals, most LDL is cleared from the circulation by LDL receptor (LDLR)-mediated endocytosis in the liver. ARH patients have a complete deficiency of hepatic LDL clearance, yet the function of the LDLR in cultured skin fibroblasts is essentially normal. The role of this putative adaptor protein in LDLR trafficking and function is a focus in my laboratory. We found that sitosterolemia is due to mutations in two coordinately regulated genes, ATP binding cassette (ABC) half-transporters, ABCG5 and ABCG8, that heterodimerize to form a sterol transporter that plays an important role in the uptake and excretion of dietary sterols. Recently, we successfully purified and reconstituted the ABCG5/ABCG8 complex and are characterizing how these proteins transport sterols across membranes. More recently we identified sequence variations in a circulating protein, a member of the proprotein convertase gene family called PCSK9, that are associated with lower plasma levels of LDL-cholesterol and protection from heart disease. This protein normally reduces LDLR activity by a yet-to-be-defined post-translational mechanism. A major goal of our laboratory is to clarify how PCSK9 promotes the degradation of the LDLR. The mechanistic studies in the laboratory are complemented by family and population-based studies in humans to examine the effects of sequence variations in the genes we identify on plasma sterol levels and risk for heart disease. We are using various genetic methods (linkage in families, expression array studies in tissues, whole genome associations and resequencing of genes) to identify new genes and sequence variations that contribute to cardiovascular disease. I serve as the director of the Dallas Heart Study, a population-based study that provides a detailed clinical database of a phenotypically well-characterized multi-ethnic population from Dallas, Texas.
RESEARCH INTERESTS
LDL metabolism
Genetic determinants of plasma lipid levels
Role of ABC transporters in lipid transport
RECENT PUBLICATIONS
Jonathan C. Cohen, Ph.D., Eric Boerwinkle, Ph.D., Thomas H. Mosley, Jr., Ph.D., and Helen H. Hobbs, M.D., "Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease." New England Journal of Medicine, 354:1310-1312, March 2006
Cohen J., Pertsemlidis A., Kotowski I.K., Graham R., Garcia C. K., Hobbs H.H., "Low LDL-cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9" Nature Genetics, 37:161-165, 2005
Yang C., Yu L., Li W., Xu F., Cohen J.C., Hobbs H.H., "Disruption of cholesterol homeostasis by phytosterols in adrenal glands of ABCG5 and ABCG8 deficient mice." J. Clin. Invest., 114:813-822, 2004
Cohen J.C., Kiss R.S., Pertsemlidis A., Marcel Y.L., McPherson R., Hobbs H.H., "Multiple rare alleles contribute to low plasma levels of HDL cholesterol." Science, 305:869-872, 2004
Michaely, P., Li, W., Anderson, R.G.W., Cohen, J.C., Hobbs, H.H., "ARH is required for LDL binding and internalization, but not for LDL receptor clustering in coated pits." J. Biol. Chem., 279:34023-31, 2004
SIGNIFICANT PUBLICATIONS
Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, Calandra S, Bertolini S, Cossu F, Grishin N, Barnes R, Cohen JC, Hobbs HH., "Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein." Science, 292:1394-1398, 2001
Berge KE, Tian H, Graf G, Yu L, Grishin NV, Schwartz J, Kwiterovich P, Shan B, Barnes R, Hobbs HH., "Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters." Science, 290:1771-1775, 2000
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