© 1997 American Heart Association, Inc.
Articles |
Regulation of Lipoprotein Metabolism by Thiazolidinediones Occurs through a Distinct but Complementary Mechanism Relative to Fibrates
From the U.325 INSERM, Département d'Athérosclérose, Institut Pasteur, 1 Rue Calmette, Lille, France; Department of Biochemistry and Molecular Biology, University of Barcelona, Spain (J.P.-O.); Ligand Pharmaceuticals Inc., San Diego, Calif (M.R.B., J.R.P.).
Correspondence to Dr. Bart Staels, INSERM U.325, Institut Pasteur, 1, rue du Prof. Calmette, 59019 Lille Cédex, France.
Abstract Thiazolidinediones are antidiabetic agents, which
not only improve glucose metabolism but also reduce blood
triglyceride concentrations. These compounds are synthetic
ligands for PPAR
, a transcription factor belonging to the nuclear
receptor subfamily of PPARs, which are important transcriptional
regulators of lipid and lipoprotein metabolism. The goal of
this study was to evaluate the influence of a potent thiazolidinedione,
BRL49653, on serum lipoproteins and to determine whether its
lipid-lowering effects are mediated by changes in the expression of key
genes implicated in lipoprotein metabolism. Treatment of
normal rats for 7 days with BRL49653 decreased serum
triglycerides in a dose-dependent fashion without affecting
serum total and HDL cholesterol and apolipoprotein (apo)
A-I and apo A-II concentrations. The decrease in
triglyceride concentrations after BRL49653 was mainly due
to a reduction of the amount of VLDL particles of unchanged lipid and
apo composition. BRL49653 treatment did not change
triglyceride production in vivo as analyzed
by injection of Triton WR-1339, indicating a primary action on
triglyceride catabolism. Analysis of the influence
of BRL49653 on the expression of LPL and apo C-III, two key players in
triglyceride catabolism, showed a dose-dependent increase
in mRNA levels and activity of LPL in epididymal adipose tissue,
whereas liver apo C-III mRNA levels remained constant. Furthermore,
addition of BRL49653 to primary cultures of differentiated adipocytes
increased LPL mRNA levels, indicating a direct action of the drug on
the adipocyte. Simultaneous administration of BRL49653 and
fenofibrate, a hypolipidemic drug that acts primarily on liver through
activation of PPAR
both decreased liver apo C-III and increased
adipose tissue LPL mRNA levels, resulting in a more pronounced lowering
of serum triglycerides than each drug alone. In conclusion,
both fibrates and thiazolidinediones exert a
hypotriglyceridemic effect. While fibrates act
primarily on the liver by decreasing apo C-III production,
BRL49653 acts primarily on adipose tissue by increasing lipolysis
through the induction of LPL expression. Drugs combining both PPAR
and activation potential should therefore display a more efficient
hypotriglyceridemic activity than either compound
alone and may provide a rationale for improved therapy for elevated
triglycerides.
Key Words: gene regulation • atherosclerosis • PPAR • triglycerides • hypolipidemic drugs
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