Am. Lefebvre et al., REGULATION OF LIPOPROTEIN METABOLISM BY THIAZOLIDINEDIONES OCCURS THROUGH A DISTINCT BUT COMPLEMENTARY MECHANISM RELATIVE TO FIBRATES, Arteriosclerosis, thrombosis, and vascular biology, 17(9), 1997, pp. 1756-1764
Thiazolidinediones are antidiabetic agents, which not only improve glu
cose metabolism but also reduce blood triglyceride concentrations. The
se compounds are synthetic ligands for PPAR gamma, a transcription fac
tor belonging to the nuclear receptor subfamily of PPARs, which are im
portant transcriptional regulators of lipid and lipoprotein metabolism
. The goal of this study was to evaluate the influence of a potent thi
azolidinedione, BRL49653, on serum lipoproteins and to determine wheth
er its lipid-lowering effects are mediated by changes in the expressio
n of key genes implicated in lipoprotein metabolism. Treatment of norm
al rats for 7 days with BRL49653 decreased serum triglycerides in a do
se-dependent fashion without affecting serum total and HDL cholesterol
and apolipoprotein (apo) A-I and apo A-II concentrations. The decreas
e in triglyceride concentrations after BRL49653 was mainly due to a re
duction of the amount of VLDL particles of unchanged lipid and apo com
position. 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 BRL49
653 on the expression of LPL and apo C-III, two key players in triglyc
eride 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 pr
imary 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 alpha both decreas
ed liver apo C-III and increased adipose tissue LPL mRNA levels, resul
ting in a more pronounced lowering of serum triglycerides than each dr
ug 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 expressio
n. Drugs combining both PPAR alpha and gamma activation potential shou
ld therefore display a more efficient hypotriglyceridemic activity tha
n either compound alone and may provide a rationale for improved thera
py for elevated triglycerides.