Int J Biol Sci 2022; 18(6):2317-2328. doi:10.7150/ijbs.69609 This issue

Research Paper

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

Zhenzhen Zhang1,2*, Tiantian Yao1*, Nan Zhao3, Hui Liu4, Hao Cheng1, Frank J Gonzalez5, Hua Wang6, Guiqiang Wang1, Aijuan Qu3, Yan Wang1✉

1. Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China.
2. Department of Hepatic Oncology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, 361015, China.
3. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing 100069, China.
4. Department of Pathology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
5. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, USA.
6. Department of Pharmacy, Anhui Medical University; Department of Oncology, the First Affiliated Hospital, Institute for Liver Diseases of Anhui Medical University, Hefei, 230032, China.
*These authors contributed equally to this work.

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Citation:
Zhang Z, Yao T, Zhao N, Liu H, Cheng H, Gonzalez FJ, Wang H, Wang G, Qu A, Wang Y. Disruption of peroxisome proliferator-activated receptor α in hepatocytes protects against acetaminophen-induced liver injury by activating the IL-6/STAT3 pathway. Int J Biol Sci 2022; 18(6):2317-2328. doi:10.7150/ijbs.69609. Available from https://www.ijbs.com/v18p2317.htm

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Abstract

Graphic 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.

Keywords: Acetaminophen (APAP), Hepatotoxicity, Peroxisome proliferator-activated receptor α (PPARα), Oxidative stress, IL-6/STAT3, Liver injury, Liver repair