Atherosclerosis 152 2000 181 – 192
Alterations in the main steps of reverse cholesterol transport in male patients with primary hypertriglyceridemia and low
HDL-cholesterol levels
Fernando D. Brites
a,
, Carla D. Bonavita
a
, Catherine De Geitere
b
, Marcelo Cloe¨s
b
, Bernard Delfly
b
, Mario J. Yael
a
, Jean-Charles Fruchart
b
, Regina W. Wikinski
a
, Graciela R. Castro
b
a
Laboratory of Lipids and Lipoproteins, Department of Clinical Biochemistry, School of Pharmacy and Biochemistry, Uni6ersity of Buenos Aires, Junin
956
, Capital Federal, C.P.
1113
Buenos Aires, Argentina
b
Ser6ice dEtude et de Recherche sur les Lipoprote´ines et lAthe´roscle´rose, Unite´
325
INSERM, Institut Pasteur de Lille, Lille, France Received 22 December 1998; received in revised form 5 October 1999; accepted 3 November 1999
Abstract
Hypertriglyceridemia is a complex pathological entity strongly connected to low HDL-C levels but controversially related to the risk of coronary artery disease. In this study, we evaluated the main steps of the antiatherogenic pathway called reverse cholesterol
transport in a group of patients with primary hypertriglyceridemia and low HDL-C levels in comparison to normotriglyceridemic subjects with or without hypoalphalipoproteinemia. In patients with primary hypertriglyceridemia, low HDL-C levels were
accompanied by decreased apo A-I and apo A-II concentrations. These reductions were manifested by a selective reduction in LpA-I:A-II particles. In addition, apo C-III Lp non B was found to be elevated and HDL lipid percentage composition showed
a triglyceride enrichment and cholesterol depletion. The capacity of serum samples from hypertriglyceridemic patients to promote cellular cholesterol efflux was reduced, as evidenced by using two different cellular models, Fu5AH and J774 cells. This impaired
cholesterol efflux promotion was also corroborated by incubations of isolated HDL fractions with Fu5AH cells. Lecithin:cholesterol acyltransferase LCAT activity, the driving force of reverse cholesterol transport, showed a tendency towards
lower values in hypertriglyceridemic patients, but this difference was not statistically significant. Additionally, cholesteryl ester transfer protein CETP activity was increased in this group of patients. Therefore, hypertriglyceridemia was found to induce
quantitative and qualitative alterations in HDL and its subclasses and, consequently, in some steps of reverse cholesterol transport. The abnormalities found in this antiatherogenic pathway and its promoters could constitute a possible connection
between hypertriglyceridemia and atherosclerosis. © 2000 Elsevier Science Ireland Ltd. All rights reserved.
Keywords
:
Hypertriglyceridemia; High density lipoproteins HDL; Hypoalphalipoproteinemia; Reverse cholesterol transport; Cholesterol efflux; Lecithin:cholesterol acyltransferase LCAT; Cholesteryl ester transfer protein CETP
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1. Introduction
Hypertriglyceridemia, defined as an increase in plasma triglyceride levels over 200 mgdl [1], is a com-
plex 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 con-
nected 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, re-
Corresponding author. Tel.: + 54-11-4964-8297; fax: + 54-11- 4508-3645.
E-mail address
:
fbritesdbc.ffyb.uba.ar F.D. Brites. 0021-915000 - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 0 2 1 - 9 1 5 0 9 9 0 0 4 5 2 - 9
sults 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 high-
lighted the strong evidence which associates hyper- triglyceridemia 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 lipo- protein families, which are comprised within chylomi-
cron 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 apolipo-
protein composition of these triglyceride rich lipo- proteins 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 trans-
port. 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 intercon-
nected 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 accep- tors
[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 trans-
fer 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 – 15]. Moreover, in a study car-
ried out in type 2 diabetic patients with moderate hypertriglyceridemia [16], we found an abnormal re-
verse cholesterol transport both in fasting and post- prandial states. Nevertheless, we were not able to find
out if the described disorders were due to hypertriglyce- ridemia itself or to the alterations associated with the
diabetic condition. Evidence then is lacking about the different steps of reverse cholesterol transport in pri-
mary hypertriglyceridemia in which no additional fac- tors can affect the lipoprotein spectrum. While it has
been suggested that LCAT and CETP activities could be determinant factors for HDL levels in hypertriglyce-
ridemic 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 hypertriglyce-
ridemia 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 an- tiatherogenic pathway.
2. Materials and methods
