Disruption of peroxisome proliferator-activated receptor α in hepatocytes protects against acetaminophen-induced liver injury by activating the IL-6/STAT3 pathway.

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.