Andras G. Lacko - US grants

No Abstract Provided

No Abstract Provided

Age related hyperlipidemia has been reported for both man and rat. However, the pathophysiology and biochemistry of this process has not yet been elucidated. The most intriguing phase of vascular lipid transport and other mechanisms involved with hyperlipidemia is reverse cholesterol transport or the return of peripheral cholesterol to the liver for disposal. High density lipoproteins (HDL) and the enzyme Lecithin:cholesterol acyltransferase (LCAT) have been jointly implicated in this reverse cholesterol transport pathway. During preliminary studies, data has been collected that consistently showed an age related decrease in the fractional rate of cholesterol esterification; a parameter related to LCAT substrate efficiency and cholesterol ester turnover. Experiments are proposed to explore the mechanism of age related hyperlipidemia in the rat, with particular focus on the role of HDL and LCAT. Specific phases of the project include, 1) Development of an immunoassay procedure for LCAT in the rat. 2) Refinement of the time course of age related changes in the rat by studying the specific parameters of plasma lipid metabolism in 12, 15, 18, 21 and 24 month old animals. 3) Study of the age related changes in the composition of the subfractions of HDL, postulated to serve as substrates for LCAT in vivo. 4) Study the age related changes that might occur in the secretion of LCAT from the liver. It is recognized that the hyperlipidemia observed in senescent animals is probably not directly related to the aging process but rather it is a secondary or tertiary development. However, the elucidation of the pathophysiology involved in age related hyperlipidemia should help in identifying the basic mechanisms involved in the aging of mammals.

The proposed research will examine the mechanism of the reaction catalyzed by the enzyme Lecithin: Cholesterol Acyltransferase (LCAT). Interaction between the enzyme and high density lipoprotein (HDL), its primary substrate in vivo, will be investigated. A newly developed method involving hydrophobic chromatography will be used for the isolation of HDL. This technique avoids some of the compositional changes that are associated with other preparative techniques, particularly ultracentrifugation. The HDL will be fractionated on DEAE cellulose into subfractions which are known to exhibit differential reactivity toward LCAT. Specific phases of the proposed research will include: 1) Incubation of the HDL subfractions with purified enzyme and examination of the LCAT reaction as a function of the concentration of substrate lipids and those of specific apoprotein components of the lipid/protein substrate complex. 2) Study of the transfer of substrate lipids from triglyceride rich lipoprotein to HDL subfractions and the effect of the attendant changes on the LCAT reaction. 3) Study of the mechanism of product (lysolecithin) removal from the enzyme surface. The LCAT/HDL system has been implicated in the process called reverse cholesterol transport which facilitates the transfer of excess cholesterol from peripheral tissues to the liver. It is thus likely that the findings of the research proposed here would aid in the understanding of the reversal of atherosclerosis. Consequently, the findings may ultimately be useful in developing modalities for the prevention of cardiovascular diseases including coronary heart disease.

Data from epidemiological studies have consistently shown that elevated levels of high density lipoproteins (HDL) are an index of protection against coronary heart disease. However, the mechanism whereby HDL is involved in the prevention and or reversal of atherosclerosis is not clear. One of the mechanisms whereby HDL has been proposed to function as a protector against atherosclerosis is referred to as reverse cholesterol transport. In this system, HDL functions jointly with the enzyme lecithin:cholesterol acyltransferase (LCAT) and the cholesteryl ester transfer protein (CETP) in a system to facilitate the clearance of cholesterol from the plasma. Although reverse cholesterol transport has originally been proposed by Glomset as a physiologically essential mechanism that returns the peripheral cholesterol to the liver, much of this hypothesis remains clinically unsubstantiated. Key elements of knowledge are still lacking that would allow the linking of cholesterol efflux from cells and tissues with specific events in HDL metabolism. the purpose of the proposed symposium is to provide a forum for the exchange of ideas particularly unpublished recent findings in this area. We held a symposium in 1989 that was very enthusiastically received in the scientific community. The proposed symposium is a continuation of the effort to promote the knowledge available on the metabolism of HDL and its relationship to atherosclerosis and coronary heart disease.