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

• DOI: 10.1016/j.jhep.2022.10.028
• Publication Date: 2022-11-09T07:26:42Z
• Authors: Shuai Chen; Zhi Lu; Haoyu Jia; Bo Yang; Chun Liu; Yuxin Yang; Shuo Zhang; Zhijing Wang; Liu Yang; Shanshan Li; Jing Li; Changqing Yang
• Keywords: Acetaminophen; FOXO1

Acetaminophen (APAP) is the most common cause of drug-induced liver injury (DILI); however, treatment options are limited. Mas a G protein-coupled receptor whose role in APAP-induced hepatotoxicity has not yet been examined.Intrahepatic expression was determined both human and mouse DILI models. Mas1-/-, AlbcreMas1f/f, Ppara-/-, Mas1-/-Ppara-/- wild-type mice were challenged with APAP for vivo analyses Mas-AKT-FOXO1 axis-dependent lipophagy fatty acid oxidation (FAO), using pharmacological compounds genetic tools. Liver samples collected RNA-sequencing, proteomics, metabolomics, lipidomics, metabolic flux analysis. Live-imaging histological, biochemical, molecular studies performed to evaluate mice. Primary hepatocytes hepatic cell lines exposed vitro analysis.Intrahepatic significantly upregulated Mice systemic, liver-specific, or hepatocyte-specific Mas1 deficiency vulnerable hepatotoxicity. They exhibited substantially impaired downstream FAO, which accompanied by activation AKT suppression FOXO1. In addition, prophylactic conferred strong protection against challenge mice, remarkably enhanced FAO dependent on AKT-FOXO1 axis. Moreover, protective effects AVE0991 diminished inhibition either FAO.The AKT-FOXO1-dependent protecting from indicating that might be novel therapeutic target DILI.Mas signalling arises as patients injury. The Mas-AKT/FOXO1-fatty degradation pathway could critical development strategies overdose. When targeted, extent should considered at time administration. These findings obtained APAP-challenged still need confirmed clinical context.