Effects of peroxisome proliferator-activated receptor alpha activation on pathways contributing to cholesterol homeostasis in rat hepatocytes.
Peroxisome proliferator-activated receptor alpha (PPARalpha) activation by fibrates controls expression of several genes involved in hepatic cholesterol metabolism. Other genes could be indirectly controlled in response to changes in cellular cholesterol availability. To further understand how fibrates may affect cholesterol synthesis, we investigated in parallel the changes in the metabolic pathways contributing to cholesterol homeostasis in liver. Ciprofibrate increased HMG-CoA reductase and FPP synthase mRNA levels in rat hepatocytes, together with cholesterogenesis from [(14)C] acetate and [(3)H] mevalonate. The up-regulation observed in fenofibrate- and WY-14,643-treated mice was abolished in PPARalpha-null mice, showing an essential role of PPARalpha. Among the three sterol regulatory element-binding protein (SREBP) mRNA species, only SREBP-1c level was significantly increased. In ciprofibrate-treated hepatocytes, cholesterol efflux was decreased, in parallel with cholesteryl ester storage and bile acids synthesis. As expected, AOX expression was strongly induced, supporting evidence of the peroxisome proliferation. Taken together, these results show that fibrates can cause cholesterol depletion in hepatocytes, possibly in part as a consequence of an important requirement of cholesterol for peroxisome proliferation, and increase cholesterogenesis by a compensatory phenomenon afterwards. Such cholesterogenesis regulation could occur in vivo, in species responsive to the peroxisome proliferative effect of PPARalpha ligands.
Le Jossic-Corcos
Catherine
C
Laboratoire de Biologie Moléculaire et Cellulaire, GDR CNRS no. 2583, Université de Bourgogne, 6 Boulevard Gabriel, 21000 Dijon, France. Catherine.Corcos@u-bourgogne.fr
Duclos
Sandrine
S
Ramirez
Leyla C
LC
Zaghini
Isabelle
I
Chevillard
Grégory
G
Martin
Pascal
P
Pineau
Thierry
T
Bournot
Paulette
P
D000085:Acetates / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002247:Carbon Isotopes; D002262:Carboxy-Lyases / Q000378:metabolism; D002455:Cell Division; D002784:Cholesterol / Q000378:metabolism*; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D058607:Fibric Acids; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
D000085:Acetates; D001647:Bile Acids and Salts; D022762:CCAAT-Enhancer-Binding Proteins; D002247:Carbon Isotopes; D004268:DNA-Binding Proteins; D058607:Fibric Acids; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C497388:Srebf1 protein, mouse; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D002995:Clofibric Acid; C006253:pirinixic acid; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002262:Carboxy-Lyases; C022503:pyrophosphomevalonate decarboxylase; C019304:ciprofibrate; D008798:Mevalonic Acid