© 1999 American Heart Association, Inc.
Original Contributions |
Developmental and Pharmacological Regulation of Apolipoprotein C-II Gene Expression
Comparison With Apo C-I and Apo C-III Gene Regulation
From U325 INSERM, Département d'Athérosclérose, Institut Pasteur de Lille et Faculté de Pharmacie, Université de Lille II, Lille, France (Y.A., Z.M., A.-M.L., G.M., J.-C.F., J.N., B.S.); and the Cardiology Research Center, Academy of Medical Sciences (V.K.), and the Moscow Coordinating Center of Organ Donation (A.V.S.), Moscow, Russia.
Correspondence to Dr Bart Staels, U325 INSERM, Institut Pasteur de Lille, 1, rue du Prof Calmette, B.P.245, 59019 Lille Cédex, France. E-mail Bart.Staels{at}pasteur-lille.fr
Abstract—Increased plasma
triglyceride concentrations are often observed in
metabolic disorders predisposing to coronary heart
disease. Among the major determinants of plasma
triglyceride metabolism are the apolipoproteins
(apos) of the C class, C-I, C-II, and C-III. Whereas
physiological concentrations of apo C-II are
required for lipolysis of triglycerides by lipoprotein
lipase (LPL), overexpression of all 3 C apolipoproteins leads to
hypertriglyceridemia. In the present
study, we investigated apo C-II gene regulation under conditions
associated with profound changes in plasma triglyceride
metabolism, ie, during postnatal development and after
treatment with the triglyceride-lowering fibrate drugs, and
compared its expression to that of apo C-I and apo C-III. Whereas the
expression of both apo C-I and apo C-III is low in fetal liver,
increases gradually after birth, and attains maximal levels after
weaning, apo C-II gene expression is already detectable in the fetal
liver, increases rapidly immediately after birth, and remains elevated
throughout suckling. Thus, the increased ingestion of lipids during
suckling is met by an earlier induction of apo C-II, the obligatory
activator for LPL, compared with apo C-III and apo C-I,
which antagonize triglyceride catabolism. Treatment of rats
with fibrates decreased apo C-II gene expression in the liver, but not
in the intestine, whereas apo C-I gene expression did not change. The
decrease of liver apo C-II mRNA levels after fenofibrate occurred in a
time- and dose-dependent manner and was reversible but appeared less
pronounced than the decrease of apo C-III mRNA. Apo C-II mRNA levels
were not affected after treatment with BRL49653, a peroxisome
proliferator–activated receptor (PPAR)
–specific ligand,
suggesting that fibrates act on apo C-II expression via PPAR
.
Addition of fenofibric acid to primary rat and human
hepatocytes resulted in a decrease of apo C-II expression.
In conclusion, fibrates decrease gene expression of apo C-II and apo
C-III, but not apo C-I, in rat and human hepatocytes. This
decrease of apo C-II and apo C-III gene expression, together with a
lowered apo C-III to apo C-II ratio, should result in an improved
clearance of triglyceride-rich remnant lipoproteins from
plasma, without hampering triglyceride lipolysis by
LPL.
Key Words: apolipoproteins • gene regulation • hypolipidemic drugs • hypertriglyceridemia • lipoprotein metabolism
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