2. Academic Validation
  3. Hepatocyte-specific Mas activation enhances lipophagy and fatty acid oxidation to protect against acetaminophen-induced hepatotoxicity in mice

Hepatocyte-specific Mas activation enhances lipophagy and fatty acid oxidation to protect against acetaminophen-induced hepatotoxicity in mice

  • J Hepatol. 2022 Nov 9;S0168-8278(22)03285-8. doi: 10.1016/j.jhep.2022.10.028.
Shuai Chen 1,  Zhi Lu 2,  Haoyu Jia 1,  Bo Yang 1,  Chun Liu 1,  Yuxin Yang 3,  Shuo Zhang 1,  Zhijing Wang 1,  Liu Yang 1,  Shanshan Li 1,  Jing Li 4,  Changqing Yang 5
Affiliations

Affiliations

  • 1 Department of Gastroenterology and Hepatology, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
  • 2 Department of Automation, Tsinghua University, Beijing 100084, China; Institute for Brain and Cognitive Sciences, Tsinghua University, Beijing 100084, China.
  • 3 Department of Automation, Tsinghua University, Beijing 100084, China.
  • 4 Department of Gastroenterology and Hepatology, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200092, China. Electronic address: [email protected].
  • 5 Department of Gastroenterology and Hepatology, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200092, China. Electronic address: [email protected].
PMID: 36368597 DOI: 10.1016/j.jhep.2022.10.028
Abstract

Background & aims: Acetaminophen (APAP) is the most common cause of drug-induced liver injury (DILI); however, treatment options are limited. Mas is a G protein-coupled receptor whose role in APAP-induced hepatotoxicity has not yet been examined.

Methods: Intrahepatic Mas expression was determined in both human and mouse DILI models. Mas1-/-, AlbcreMas1f/f, Ppara-/-, Mas1-/-Ppara-/- and wild-type mice were challenged with APAP for the in vivo analyses of Mas-AKT-FOXO1 axis-dependent lipophagy and fatty acid oxidation (FAO), using pharmacological compounds and genetic tools. Liver samples were collected for RNA-sequencing, proteomics, metabolomics, lipidomics, and metabolic flux analysis. Live-imaging of liver and histological, biochemical, and molecular studies were performed to evaluate APAP-induced hepatotoxicity in mice. Primary hepatocytes and hepatic cell lines were exposed to APAP for in vitro analysis.

Results: Intrahepatic Mas expression was significantly upregulated in human and mouse DILI models. Mice with systemic, liver-specific, or hepatocyte-specific Mas1 deficiency were vulnerable to APAP-induced hepatotoxicity. They exhibited substantially impaired lipophagy and downstream FAO, which was accompanied by the activation of Akt and suppression of FOXO1. In addition, the prophylactic activation of Mas showed unbelievably ideal effects to protect mice from APAP challenge, with remarkably enhanced lipophagy and FAO dependent on the AKT-FOXO1 axis. Moreover, the protective effects of AVE0991 were substantially diminished by the inhibition of either lipophagy or FAO.

Conclusions: The activation of Mas on hepatocytes enhanced AKT-FOXO1-dependent lipophagy and downstream FAO to protect mice from APAP-induced hepatotoxicity, suggesting that hepatocyte-specific Mas might be a novel therapeutic target for DILI.

Impact and implications: Mas signaling arises as a novel therapeutic target for patients with APAP overdose. Mas-AKT/FOXO1-fatty acid degradation pathway is critical for researchers to develop treatment strategies of APAP overdose. When Mas signaling is targeted, the extent of liver injury should be taken into account at the time of administration. These findings obtained from APAP-challenged mice still need to be confirmed in the clinics.

Keywords

Mas; acute liver failure; fatty acid degradation; sterile inflammation.

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