Lecithin:cholesterol acyltransferase (LCAT) is the major cholesterol esterifying activity of human plasma. It is important in the remodeling of nascent high density lipoproteins (HDL), which are rich in free cholesterol, into mature HDL in which most of the cholesterol is in its esterified form. This process is important in the transport of cholesterol from peripheral tissues to the liver where a portion of the cholesterol if converted to bile salts. This """"""""reverse cholesterol transport"""""""" is an important step in prevention and regression of atherosclerosis. This project will focus upon two important areas; LCAT regulation and structure- function relationships. The first step will be to investigate in rats, isolated rat hepatocytes, and human hepatoma cells the influence that diets which are known to affect plasma LCAT levels have on LCAT mRNA, synthesis, and secretion. The effects of dietary triglycerides containing n-3 fatty acids, which alter plasma LCAT levels in man, on plasma LCAT levels, LCAT secretion, and turnover will be compared with those of control rats given conventional chow or triglycerides with n-9 fatty acids. Cultures of human hepatoma cells will be used to directly compared the effects of n-3 and n-6 fatty acids in albumin complexes and in model reassembled HDL in which the test fatty acids are located at the sn-2 position of phosphatidylcholine. The effects of the free cholesterol and cholesteryl ester contents of the model HDL will also be determined. The second step will be to use site- directed mutagenesis and monoclonal antibodies to unambiguously identify some of the functional regions of LCAT and to determine the molecular basis of its substrate specificity, which is different in different mammalian species. These studies will delineate the mechanism by which LCAT forms cholesteryl esters, better localize the region(s) responsible for binding to lipoprotein surfaces, and reveal differences in the active site region of LCAT from different species that have different substrate specificities.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL030914-08
Application #
3341918
Study Section
Metabolism Study Section (MET)
Project Start
1983-07-01
Project End
1994-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
8
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
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Pownall, Henry J; Gotto Jr, Antonio M (2016) New Insights into the High-Density Lipoprotein Dilemma. Trends Endocrinol Metab 27:44-53
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Rosales, Corina; Patel, Niket; Gillard, Baiba K et al. (2015) Apolipoprotein AI deficiency inhibits serum opacity factor activity against plasma high density lipoprotein via a stabilization mechanism. Biochemistry 54:2295-302
Pownall, Henry J; Bray, George A; Wagenknecht, Lynne E et al. (2015) Changes in body composition over 8 years in a randomized trial of a lifestyle intervention: the look AHEAD study. Obesity (Silver Spring) 23:565-72
Pownall, Henry J; Gillard, Baiba K; Gotto Jr, Antonio M (2013) Setting the course for apoAII: a port in sight? Clin Lipidol 8:551-560
Vasudevan, Madhuri; Tchoua, Urbain; Gillard, Baiba K et al. (2013) Modest diet-induced weight loss reduces macrophage cholesterol efflux to plasma of patients with metabolic syndrome. J Clin Lipidol 7:661-70
Gillard, Baiba K; Raya, Joe L; Ruiz-Esponda, Raul et al. (2013) Impaired lipoprotein processing in HIV patients on antiretroviral therapy: aberrant high-density lipoprotein lipids, stability, and function. Arterioscler Thromb Vasc Biol 33:1714-21
Wooten, Joshua S; Nambi, Preethi; Gillard, Baiba K et al. (2013) Intensive lifestyle modification reduces Lp-PLA2 in dyslipidemic HIV/HAART patients. Med Sci Sports Exerc 45:1043-50

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