Abstract |
Background & Aims: Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor abundantly expressed in liver. PPARα activator has been previously reported to protect against acetaminophen-induced hepatotoxicity, but fenofibrate, a lipid-lowering drug that activates PPARα, has a common side-effect causing liver injury. Thus, the exact effect of liver PPARα on drug-induced liver injury remains obscure. Methods: Hepatocyte-specific Ppara knockout mice and littermate wild-type control mice were intraperitoneally injected with acetaminophen (400 mg/kg body weight). Blood and liver samples were collected at different time points. We measured phase I and II cytochrome P450 enzymes, glutathione, reactive oxygen species, cytokines including Il6, and pSTAT3 by reverse transcriptase quantitative PCR, colorimetric, immunohistochemistry analyses and Western blotting. Results: Hepatic expression of PPARα was significantly decreased in DILI patients. Disruption of the Ppara gene in hepatocytes significantly reduced acetaminophen-induced liver injury in mice. ROS production rather than the expression levels of phase I and II cytochrome P450 enzymes was reduced in hepatocyte-specific Ppara knockout mice compared to control mice after acetaminophen administration. Mechanistically, hepatocyte-specific Ppara knockout mice had upregulated activation of the hepatoprotective pathway IL-6/STAT3 compared to wild-type mice, as evidenced by hepatic Il6 mRNA levels, hepatic protein levels of STAT3 and phosphorylated STAT3 were much higher in hepatocyte-specific Ppara knockout mice than in wild-type mice post acetaminophen injection. Conclusions: Hepatocyte-specific disruption of the Ppara gene protects against acetaminophen-induced liver injury by reducing oxidative stress and upregulating the hepatoprotective IL-6/STAT3 signaling pathway.
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Authors | Zhenzhen Zhang, Tiantian Yao, Nan Zhao, Hui Liu, Hao Cheng, Frank J Gonzalez, Hua Wang, Guiqiang Wang, Aijuan Qu, Yan Wang |
Journal | International journal of biological sciences
(Int J Biol Sci)
Vol. 18
Issue 6
Pg. 2317-2328
( 2022)
ISSN: 1449-2288 [Electronic] Australia |
PMID | 35414769
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © The author(s). |
Chemical References |
- Interleukin-6
- PPAR alpha
- STAT3 Transcription Factor
- STAT3 protein, human
- Acetaminophen
- Cytochrome P-450 Enzyme System
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Topics |
- Acetaminophen
(toxicity)
- Animals
- Chemical and Drug Induced Liver Injury
(metabolism)
- Chemical and Drug Induced Liver Injury, Chronic
(metabolism)
- Cytochrome P-450 Enzyme System
(metabolism)
- Hepatocytes
(metabolism)
- Interleukin-6
(metabolism)
- Liver
(metabolism)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- PPAR alpha
(genetics, metabolism)
- STAT3 Transcription Factor
(genetics, metabolism)
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