Rifampicin-Induced Hepatic Lipid Accumulation: Association with Up-Regulation of Peroxisome Proliferator-Activated Receptor γ in Mouse Liver.
Previous study found that rifampicin caused intrahepatic cholestasis. This study investigated the effects of rifampicin on hepatic lipid metabolism. Mice were orally administered with rifampicin (200 mg/kg) daily for different periods. Results showed that serum TG level was progressively reduced after a short elevation. By contrast, hepatic TG content was markedly increased in rifampicin-treated mice. An obvious hepatic lipid accumulation, as determined by Oil Red O staining, was observed in mice treated with rifampicin for more than one week. Moreover, mRNA levels of Fas, Acc and Scd-1, several key genes for fatty acid synthesis, were elevated in rifampicin-treated mice. In addition, the class B scavenger receptor CD36 was progressively up-regulated by rifampicin. Interestingly, hepatic SREBP-1c and LXR-α, two important transcription factors that regulate genes for hepatic fatty acid synthesis, were not activated by rifampicin. Instead, hepatic PXR was rapidly activated in rifampicin-treated mice. Hepatic PPARγ, a downstream target of PXR, was transcriptionally up-regulated. Taken together, the increased hepatic lipid synthesis and uptake of fatty acids from circulation into liver jointly contribute to rifampicin-induced hepatic lipid accumulation. The increased uptake of fatty acids from circulation into liver might be partially attributed to rifampicin-induced up-regulation of PPARγ and its target genes.
First Affiliated Hospital, Anhui Medical University, Hefei, China.
Jia-Hui
JH
Huang
Department of Toxicology, Anhui Medical University, Hefei, China.
Cheng
C
Zhang
First Affiliated Hospital, Anhui Medical University, Hefei, China.
Da-Gang
DG
Zhang
First Affiliated Hospital, Anhui Medical University, Hefei, China.
Lu
L
Li
First Affiliated Hospital, Anhui Medical University, Hefei, China.
Xi
X
Chen
Department of Toxicology, Anhui Medical University, Hefei, China.
De-Xiang
DX
Xu
D000103:Acetyl-CoA Carboxylase / Q000235:genetics; D000818:Animals; D004334:Drug Administration Schedule; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000235:genetics*; D012293:Rifampin / Q000008:administration & dosage* / Q000494:pharmacology; D013230:Stearoyl-CoA Desaturase / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation; D019014:fas Receptor / Q000235:genetics
C491899:Fas protein, mouse; D047495:PPAR gamma; D019014:fas Receptor; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D000103:Acetyl-CoA Carboxylase; D012293:Rifampin