| First Author | Zhang Z | Year | 2022 |
| Journal | Int J Biol Sci | Volume | 18 |
| Issue | 6 | Pages | 2317-2328 |
| PubMed ID | 35414769 | Mgi Jnum | J:323410 |
| Mgi Id | MGI:7261982 | Doi | 10.7150/ijbs.69609 |
| Citation | Zhang Z, et al. (2022) Disruption of peroxisome proliferator-activated receptor alpha in hepatocytes protects against acetaminophen-induced liver injury by activating the IL-6/STAT3 pathway. Int J Biol Sci 18(6):2317-2328 |
| abstractText | Background & Aims: Peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand-activated transcription factor abundantly expressed in liver. PPARalpha activator has been previously reported to protect against acetaminophen-induced hepatotoxicity, but fenofibrate, a lipid-lowering drug that activates PPARalpha, has a common side-effect causing liver injury. Thus, the exact effect of liver PPARalpha 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 PPARalpha 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. |
