REGULATION OF HIGH DENSITY LIPOPROTEIN METABOLISM BY CHOLESTEROL AND FATTY ACIDS

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The long-term objectives are to determine the biochemical mechanisms by which dietary factors regulate plasma lipoprotein metabolism in animal models. The laboratory is particularly interested in how dietary cholesterol and dietary fatty acids regulate the metabolism of high density lipoproteins (HDL). These lipoproteins are believed to be antiatherogenic, because they remove excess cholesterol from peripheral cells and transport it through the circulatory system as cholesteryl esters to the liver where it is degraded. This reverse cholesterol transport process is important in regulating intracellular and plasma cholesterol concentrations and, thereby, the development of atherosclerosis. HDL and HDL cholesterol (HDL-C) concentrations decrease in cholesterol-fed rabbits, but do not change in either jojoba oil- or cholesterol + jojoba oil-fed rabbits. The objective of the proposed research plan is to provide a biochemical explanation for the reduction in HDL-C concentration in cholesterol-fed rabbits and the maintenance of HDL- C at high levels in cholesterol + jojoba oil-fed rabbits. It is our hypothesis that it is the fatty acid component in jojoba oil, possibly eicosenoate (20:1), that is the active moiety and that it decreases the activity of cholesterol ester transfer protein (CETP) in the cholesterol + jojoba oil-fed rabbit. The hypothesis predicts that a high CETP activity in the cholesterol-fed rabbit decreases HDL2 cholesterol concentration and a low CETP activity in the cholesterol + jojoba oil-fed rabbit increases it. This research proposal is designed to test the validity of this hypothesis as well as to provide a biochemical explanation for the opposing actions of dietary cholesterol and dietary cholesterol + jojoba oil on HDL-C metabolism. The specific aims of the research project are (i) to identify the molecular component of jojoba oil (wax, alcohol, or fatty acid) that alters HDL-C concentration in cholesterol-fed rabbits, (ii) to determine whether or not the transfer activity of CETP or the enzymatic activity of hepatic lipase (HL) or lipoprotein lipase (LPL) change in rabbits fed either a cholesterol-rich diet or a cholesterol + jojoba oil- rich diet, and (iii) to identify the HDL subclasses (HDL1, HDL2, HDL3) whose cholesterol contents decrease in cholesterol-fed rabbits and increase in cholesterol + jojoba oil-fed rabbits. These aims will be achieved by measuring and comparing (i) the total cholesterol (free cholesterol + cholesteryl ester) concentration in the HDL fraction of rabbits fed either a normal rabbit chow diet or one supplemented with 1% cholesterol or 1% cholesterol + 2% jojoba oil or 1% cholesterol + 1% alcohol component of jojoba oil or 1% cholesterol + 1% fatty acid component of jojoba oil for 14 days, (ii) the activity of GETP, HL, and LPL in rabbits fed these five experimental diets, and (iii) the total cholesterol concentration in the HDL subclasses of rabbits in these five dietary groups. If the fatty acid moiety of jojoba oil is the active agent and it regulates the activity of CETP, HL; or LPL, then future studies will establish the fatty acid specificity of the reaction. If it does not alter their activity, then its impact on the enzymatic activity of lecithin:cholesterol acyltransferase (LCAT) will be tested. The information collected will be used either to formulate a mechanism of action that explains how dietary cholesterol and dietary cholesterol + jojoba oil regulate the metabolism of HDL-C in the plasma or to propose a new hypothesis on how these dietary factors may regulate HDL-C metabolism. An understanding of the biochemical mechanisms by which dietary cholesterol and dietary cholesterol + jojoba oil regulate the metabolism of HDL and the cholesterol content in these anti-atherogenic lipoproteins would improve our knowledge of how dietary factors regulate the induction of atherosclerosis in the rabbit as well as its possible regulation in humans.