Rifampicin-Induced Hepatic Lipid Accumulation: Association with Up-Regulation of Peroxisome Proliferator-Activated Receptor γ in Mouse Liver

Abstract

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.

Hepatotoxic effect of Rifampicin as an Anti-Tuberculosis drug on male Albino rat

“…20 In the treatment regimen of tuberculosis, RIF is the first-line drug, but exerts sever hepatototoxicity after its administration. 21 The present study indicated that all the toxicity related marker enzymes like ALT, AST. ALP and LDH (Fig.…”

“…Previously, it was reported that RIF mediated liver damage is done by increasing oxidative stress in mitochondria, apoptotic response of liver cell, cholestasis effects, and hepatic lipid accumulation in rodent. 21 The accumulation of lipid in hepatic cells is made via upregulation of peroxisome proliferators activated receptor gamma (PPAR). Recently, Kim et al 9 had observed that upregulation of PPAR stimulates the expression of five proteins (apolipoprotein C-III, acyl-CoA-binding protein, 3-ketoacyl-CoA thiolase A and B, and perilipin-2) related to lipid metabolism.…”

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury

“…Lipid accumulation is upregulated by PPARγ activation. Treatment with rifampicin (200 mg/kg) in mice for 4 weeks results in elevated hepatic lipids caused by induction of PPARγ through rifampicin-mediated activation of pregnane X receptor (PXR) [30]. A recent toxico-proteomics study suggests that the PPARγ signaling pathway is involved in rifampicin-induced liver injury [31].…”

4β-hydroxycholesterol is a pro-lipogenic factor that promotes SREBP1c expression and activity through Liver X-receptor

“…Our data points to the importance of the enzyme that produces 4b-HC, Cyp3A4 (Cyp3A11 in mice) (Bodin et al, 2001), as a crucial regulator of lipogenesis. Consistent with that, several groups have reported that increased Cyp3A4 expression by over expressing its activator, Pregnane X Receptor (PXR), correlated with increases lipogenic gene expression as well as liver triglyceride levels (Huang et al, 2016;Zhou et al, 2006). Conversely, decreased Cyp3A4 expression (He et al, 2013) or its pharmacological inhibition (Chudnovskiy et al, 2014) were associated with lower lipogenic gene expression and liver triglyceride levels.…”