Alterations in the main steps of reverse cholesterol transport in male patients with primary hypertriglyceridemia and low HDL-cholesterol levels
Introduction
Hypertriglyceridemia, defined as an increase in plasma triglyceride levels over 200 mg/dl [1], is a complex entity which can be of primary origin or secondary to any other factor or pathological condition capable of producing a lipid disorder.
Plasma triglyceride levels have been related to the concentration of cholesterol transported in high density lipoproteins (HDL-C) and to the risk of coronary artery disease (CAD) [2], [3]. HDL-C levels and CAD risk show a strong negative association; triglyceride concentration and CAD risk exhibit a weak positive relation; and HDL-C and triglyceride levels are connected in a solid inverse way. Thus, while HDL-C stands as a manifest antiatherogenic factor [4], the direct intervention of triglycerides in the genesis of atherosclerosis still remains controversial. However, results from a meta-analysis based on 17 different studies suggest that triglycerides are a risk factor for CAD, independent of HDL-C [5]. More recently, a consensus about the treatment of hypertriglyceridemia also highlighted the strong evidence which associates hypertriglyceridemia and increased CAD risk [6].
In hypertriglyceridemia, diverse lipoprotein particles seem to be affected. The increase in plasma triglyceride levels reflects an accumulation of two overlapping lipoprotein families, which are comprised within chylomicron and VLDL flotation densities: those containing apolipoprotein (apo) B and apo C-III (LpB:C-III) and those with apo B and apo E (LpB:E). Furthermore, not only the concentration, but also the lipid and apolipoprotein composition of these triglyceride rich lipoproteins were proven to be abnormal [7]. On the other hand, hypertriglyceridemia may also influence any of the two HDL subclasses: those which contain apo A-I without apo A-II (LpA-I) and those with apo A-I and apo A-II (LpA-I:A-II), two different metabolic entities [8]. HDL subclasses may also be classified according to their apo C-III or apo E content, and are identified as apo C-III Lp non B or apo E Lp non B.
Concerning the physiological function that HDL has in cholesterol transport within the organism, Glomset [9] was the first to recognize its participation in the antiatherogenic process called reverse cholesterol transport. This metabolic pathway is responsible for the movement of excess cholesterol from peripheral tissues to the liver for lipoprotein recycling or excretion and could be defined as a progression of closely interconnected events [10]. Among them, four steps are pointed out as the most relevant ones: (1) free cholesterol efflux from extrahepatic cells and its uptake by initial acceptors [11]; (2) free cholesterol esterification by lecithin:cholesterol acyltransferase (LCAT); (3) transfer of newly synthesized cholesteryl esters from HDL to apo B-containing lipoproteins and interchange with triglycerides, carried out by the cholesteryl ester transfer protein (CETP); and (4) hepatic uptake of cholesteryl esters so formed [12].
In hypertriglyceridemic patients, different authors have described quantitative and qualitative variations in lipids and apolipoproteins transported in HDL and its subpopulations [13], [14], [15]. Moreover, in a study carried out in type 2 diabetic patients with moderate hypertriglyceridemia [16], we found an abnormal reverse cholesterol transport both in fasting and postprandial states. Nevertheless, we were not able to find out if the described disorders were due to hypertriglyceridemia itself or to the alterations associated with the diabetic condition. Evidence then is lacking about the different steps of reverse cholesterol transport in primary hypertriglyceridemia in which no additional factors can affect the lipoprotein spectrum. While it has been suggested that LCAT and CETP activities could be determinant factors for HDL levels in hypertriglyceridemic patients [17], cholesterol efflux promotion has not been fully examined before. If hypertriglyceridemia demonstrably affected the whole reverse cholesterol transport, the protective role of this pathway would be deteriorated, thus contributing to the understanding of the controversial relationship between hypertriglyceridemia and atherogenicity.
In view of these considerations, the aim of the present study was to explore the first three steps of reverse cholesterol transport and especially the capacity to promote cholesterol efflux from two different cellular models in primary hypertriglyceridemic patients. We also characterized the lipoprotein, apolipoprotein and lipoprotein particle environment concerned in this antiatherogenic pathway.
Section snippets
Subjects
We studied 36 male subjects aged between 21 and 65 years old. Subjects were recruited consecutively during a period of about 6 months from Hospital de Clı́nicas José de San Martı́n, University of Buenos Aires. Subjects were included in the present study when they satisfied the following criteria previously described [7]: (1) lack of abnormalities in carbohydrate metabolism evidenced by plasma levels of fasting glucose, HbA1c, insulin and an oral glucose tolerance test; (2) normal thyroid
Results
In this study, we evaluated a group of patients with primary hypertriglyceridemia and low HDL-C levels (group 1, n=12). Results were analyzed in comparison both to a group of subjects who exhibited normal plasma triglyceride and low HDL-C levels (group 2, n=12) and to normotriglyceridemic subjects with normal HDL-C levels (group 3, controls, n=12).
All the subjects were of similar age (47±11, 40±14, 41±12 years, mean±S.D.; groups 1, 2 and 3, respectively). The body mass index was moderately
Discussion
In this study, we evaluated diverse parameters involved in reverse cholesterol transport and the first three steps that make up this antiatherogenic pathway in a group of patients with primary hypertriglyceridemia and low HDL-C levels (group 1), in comparison to normotriglyceridemic subjects with or without hypoalphalipoproteinemia (groups 2 and 3, respectively). Hypertriglyceridemia was found to induce quantitative and qualitative alterations in HDL and its subclasses and, consequently, in all
Acknowledgements
Carla D. Bonavita is a Research Fellow from University of Buenos Aires. This work was supported by a grant from the same university (FA 085) and it was part of the INSERM-CONICET International Cooperation Program.
References (49)
Triglyceride-rich lipoproteins and atherosclerosis
Atherosclerosis
(1994)- et al.
VLDL compositional changes and plasma levels of triglycerides and high density lipoprotein
Clin. Chim. Acta
(1998) The plasma lecithin:cholesterol acyltransferase reaction
J. Lipid Res.
(1968)- et al.
Molecular physiology of reverse cholesterol transport
J. Lipid Res.
(1995) - et al.
Levels and physicochemical properties of lipoprotein subclasses in moderate hypertriglyceridemia
Clin. Chim. Acta
(1993) Phosphorus assay column chromatography
J. Biol. Chem.
(1959)- et al.
LDL (low-density-lipoprotein) cholesterol determination in blood serum following precipitation of LDL with poly(vinil sulphate)
Clin. Chim. Acta
(1984) - et al.
Apolipoproteins C-III and E in apoB- and non-apoB-containing lipoproteins in two populations at contrasting risk for myocardial infarction: the ECTIM Study
J. Lipid Res.
(1996) - et al.
Protein measurement with the Folin phenol reagent
J. Biol. Chem.
(1951) - et al.
Characterization of proteoliposomes containing apoprotein A-I: a new substrate for the measurement of lecithin:cholesterol acyltransferase activity
J. Lipid Res.
(1982)
Central obesity and coronary heart disease in men
Lancet
Abnormal capacity to induce cholesterol efflux and a new LpA-I pre-β particle in type 2 diabetic patients
Clin. Chim. Acta
Cholesterol efflux from cultured adipose cells is mediated by LpA-I particles but not by LpA-I:A-II particles
Biochem. Biophys. Res. Commun.
The effects of subfractions of high density lipoprotein on cholesterol efflux from cultured fibroblasts. Regulation of low density lipoprotein receptor activity
J. Biol. Chem.
Apolipoproteins, membrane cholesterol domains and regulation of cholesterol efflux
J. Lipid Res.
Cholesterol efflux from Fu5AH hepatoma cells induced by plasma of subjects with or without coronary artery disease and non-insulin-dependent diabetes: importance of LpA-I:A-II particles and phospholipid transfer protein
Atherosclerosis
Pre-β HDL: structure and metabolism
Biochim. Biophys. Acta
Interaction of free apolipoproteins with macrophages
J. Biol. Chem.
Efflux of lipid from fibroblasts to apolipoproteins: dependence on elevated levels of cellular unesterified cholesterol
J. Lipid Res.
The hypertriglyceridemias: risk and management
Am. J. Cardiol.
Epidemiology of triglycerides: a view from Framingham
Am. J. Cardiol.
High-density lipoprotein — the clinical implications of recent studies
New Engl. J. Med.
Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies
J. Cardiovasc. Risk
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