Role of Lp A-I and Lp A-I/A-II in cholesteryl ester transfer protein-mediated neutral lipid transfer. Studies in normal subjects and in hypertriglyceridemic patients before and after fenofibrate therapy.

The two major subclasses of HDL contain apo A-I only (Lp A-I) or both apo A-I and apo A-II (Lp A-I/A-II). We have carried out experiments to quantify the participation of Lp A-I and Lp A-I/A-II in the neutral lipid transfer reaction in normal and hypertriglyceridemic subjects. Thirteen hypertriglyceridemic subjects were studied before and after fenofibrate therapy. Fenofibrate treatment resulted in decreases in total cholesterol, triglycerides (TG), and VLDL cholesterol of 19%, 48%, and 70%, respectively, and a 28% increase in HDL cholesterol, with no significant change in the proportion of Lp A-I and Lp A-I/A-II particles. The abundance of cholesteryl ester transfer protein (CETP) mRNA in peripheral adipose tissue decreased with treatment in four of five patients studied; however, no change occurred in plasma CETP mass. Using an isotopic transfer assay, we demonstrated that both Lp A-I and Lp A-I/A-II participated in the CE transfer reaction, with no change after fenofibrate therapy. This finding suggests that the marked increase in HDL cholesterol during fenofibrate therapy is due to normalization of plasma TG and hence decreased opportunity for mass transfer of lipid between HDL and TG-rich proteins in vivo. In this population of hypertriglyceridemic subjects, CETP was distributed in both the Lp A-I and Lp A-I/A-II subfractions of HDL, with preferential association with the smaller Lp A-I poor. In contrast, in nine normal subjects studied, negligible amounts of CETP were associated with Lp A-I/A-II. Nonetheless, the Lp A-I/A-II fraction of HDL contributed significantly to total CE mass transfer in normolipidemic plasma. Lp A-I/A-II is an efficient donor for CE transfer to TG-rich lipoproteins, and its low affinity for CETP may in fact facilitate neutral lipid transfer either by a shuttle mechanism or by formation of a ternary complex.

[1]  M. McDonnell,et al.  Cholesteryl ester transfer protein (CETP) mRNA abundance in human adipose tissue: relationship to cell size and membrane cholesterol content. , 1995, Journal of lipid research.

[2]  D. Epps,et al.  Kinetics and inhibition of lipid exchange catalyzed by plasma cholesteryl ester transfer protein (lipid transfer protein). , 1995, Biochemistry.

[3]  F. Follath,et al.  Plasma triglycerides and three lipoprotein cholesterol fractions are independent predictors of the extent of coronary atherosclerosis. , 1994, Circulation.

[4]  A. Tall,et al.  Gender effects on the distribution of the cholesteryl ester transfer protein in apolipoprotein A-I-defined lipoprotein subpopulations. , 1994, Journal of lipid research.

[5]  S. Yokoyama,et al.  Selective transfer of cholesteryl ester over triglyceride by human plasma lipid transfer protein between apolipoprotein-activated lipid microemulsions. , 1994, Biochemistry.

[6]  B. Föger,et al.  High density lipoproteins with differing apolipoproteins: relationships to postprandial lipemia, cholesteryl ester transfer protein, and activities of lipoprotein lipase, hepatic lipase, and lecithin: cholesterol acyltransferase. , 1994, Journal of lipid research.

[7]  A. Tall,et al.  Adipose tissue cholesteryl ester transfer protein mRNA in response to probucol treatment: cholesterol and species dependence. , 1993, Journal of lipid research.

[8]  E. Rassart,et al.  Point mutagenesis of carboxyl-terminal amino acids of cholesteryl ester transfer protein. Opposite faces of an amphipathic helix important for cholesteryl ester transfer or for binding neutralizing antibody. , 1993, The Journal of biological chemistry.

[9]  D. Bilheimer,et al.  Insulin stimulates receptor-mediated uptake of apoE-enriched lipoproteins and activated alpha 2-macroglobulin in adipocytes. , 1993, The Journal of biological chemistry.

[10]  A. Tall,et al.  Identification of a sequence within the C-terminal 26 amino acids of cholesteryl ester transfer protein responsible for binding a neutralizing monoclonal antibody and necessary for neutral lipid transfer activity. , 1992, The Journal of biological chemistry.

[11]  P. Barter,et al.  Changes in the size of reconstituted high density lipoproteins during incubation with cholesteryl ester transfer protein: the role of apolipoproteins. , 1992, Journal of lipid research.

[12]  C. Mann,et al.  Mechanism of plasma cholesteryl ester transfer in hypertriglyceridemia. , 1991, The Journal of clinical investigation.

[13]  D. Rader,et al.  In vivo metabolism of apolipoprotein A-I on high density lipoprotein particles LpA-I and LpA-I,A-II. , 1991, Journal of lipid research.

[14]  A. Tall,et al.  Plasma concentrations of cholesteryl ester transfer protein in hyperlipoproteinemia. Relation to cholesteryl ester transfer protein activity and other lipoprotein variables. , 1991, Arteriosclerosis and thrombosis : a journal of vascular biology.

[15]  C. Fielding,et al.  Distribution and functions of lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein in plasma lipoproteins. Evidence for a functional unit containing these activities together with apolipoproteins A-I and D that catalyzes the esterification and transfer of cell-derived choleste , 1989, The Journal of biological chemistry.

[16]  J. Fruchart,et al.  Effect of fenofibrate treatment on type III hyperlipoproteinemia. , 1987, The American journal of medicine.

[17]  J. Fruchart,et al.  Apolipoprotein A-I containing lipoproteins in coronary artery disease. , 1987, Atherosclerosis.

[18]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[19]  J. Fruchart,et al.  Cholesterol efflux from cultured adipose cells is mediated by LpAI particles but not by LpAI:AII particles. , 1987, Biochemical and biophysical research communications.

[20]  J. Albers,et al.  Distribution and localization of lecithin:cholesterol acyltransferase and cholesteryl ester transfer activity in A-I-containing lipoproteins. , 1986, Journal of lipid research.

[21]  Morton Re.  Binding of plasma-derived lipid transfer protein to lipoprotein substrates: the role of binding in the lipid transfer process , 1985 .

[22]  B. Lewis,et al.  An alternative procedure for incorporating radiolabelled cholesteryl ester into human plasma lipoproteins in vitro. , 1985, The Biochemical journal.

[23]  J. Albers,et al.  Characterization of lipoprotein particles isolated by immunoaffinity chromatography. Particles containing A-I and A-II and particles containing A-I but no A-II. , 1984, The Journal of biological chemistry.

[24]  D. B. Zilversmit,et al.  A plasma inhibitor of triglyceride and cholesteryl ester transfer activities. , 1981, The Journal of biological chemistry.

[25]  I. Benzie.  An evaluation of a routine assay of serum high-density lipoprotein cholesterol using dextran sulphate and magnesium chloride. , 1979, Medical laboratory sciences.

[26]  A. Tall,et al.  Plasma kinetics of cholesteryl ester transfer protein in the rabbit. Effects of dietary cholesterol. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[27]  A. Tall,et al.  Distribution and concentration of cholesteryl ester transfer protein in plasma of normolipemic subjects. , 1990, The Journal of clinical investigation.