Peroxisome proliferator-activated receptor alpha agonists regulate cholesterol ester transfer protein.
Peroxisome proliferator-activated receptor alpha (PPARalpha) belongs to the nuclear receptor superfamily that regulates multiple target genes involved in lipid metabolism. Cholesterol ester transfer protein (CETP) is a secreted glycoprotein that modifies high-density lipoprotein (HDL) particles. In humans, plasma CETP activity is inversely correlated with HDL cholesterol levels. We report here that PPARalpha agonists increase CETP mRNA, protein and accordingly its activity. In a human CETP transgenic animal model harboring the natural flanking regions (Jiang et al. in J Clin Investigat 90:1290-1295, 1992), both fenofibrate and a specific synthetic PPARalpha agonist LY970 elevated human CETP mRNA in liver, serum protein and CETP activity. In hamsters, the endogenous liver CETP mRNA level and the serum CETP activity were dose-dependently upregulated by fenofibrate. In addition Wy14643, a PPARalpha agonist, also significantly elevated CETP mRNA and activity. In a carcinoma cell line of hepatic origin, HepG2 cells, overexpression of PPARalpha resulted in increased CETP mRNA and agonist treatment further elevated CETP mRNA levels. We conclude that PPARalpha agonists upregulate CETP expression and activity and may play an important role in PPARalpha (agonist mediated HDL cholesterol homeostasis in humans.
Beyer
Thomas P
TP
Cardiovascular Research, Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN 46285, USA.
Chen
Yanqun
Y
Porter
Regina K
RK
Lu
Deshun
D
Schmidt
Robert J
RJ
Mantlo
Nathan B
NB
Konrad
Robert J
RJ
Cao
Guoqing
G
D000818:Animals; D002478:Cells, Cultured; D053480:Cholesterol Ester Transfer Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D011345:Fenofibrate / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis
D053480:Cholesterol Ester Transfer Proteins; D047493:PPAR alpha; D012333:RNA, Messenger; D011345:Fenofibrate