Loss of long-chain acyl-CoA synthetase 1 promotes hepatocyte death in alcohol-induced steatohepatitis

• Published in: Metabolism, clinical and experimental Vol. 138; p. 155334
• Main Authors: Dong, Haibo, Zhong, Wei, Zhang, Wenliang, Hao, Liuyi, Guo, Wei, Yue, Ruichao, Sun, Xinguo, Sun, Zhaoli, Bataller, Ramon, Zhou, Zhanxiang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2023
• Subjects: ACSL1; Alcohol-associated liver disease; Animals; Cell death; Chemical and Drug Induced Liver Injury, Chronic - metabolism; Coenzyme A Ligases - genetics; Ethanol - toxicity; Fatty Acids - metabolism; Fatty Acids, Nonesterified - metabolism; Fatty Liver - metabolism; Free fatty acids; Hepatocytes - metabolism; Lysosomal membrane permeabilization; Mice; Mice, Knockout; STAT5; STAT5 Transcription Factor - metabolism; Lysosomal membrane permeabilization; STAT5; ACSL1; Cell death; Alcohol-associated liver disease; Free fatty acids
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2022.155334

Alcohol consumption has been shown to disrupt hepatic lipid homeostasis. Long-chain acyl-CoA synthetase 1 (ACSL1) critically regulates hepatic fatty acid metabolism and lipid homeostasis by channeling fatty acids to lipid metabolic pathways. However, it remains unclear how ACSL1 contributes to the development of alcohol-associated liver disease (ALD). We performed chronic alcohol feeding animal studies with hepatocyte-specific ACSL1 knockout (ACSL1Δhep) mice, hepatocyte-specific STAT5 knockout (STAT5Δhep) mice, and ACSL1Δhep based-STAT5B overexpression (Stat5b-OE) mice. Cell studies were conducted to define the causal role of ACSL1 deficiency in the pathogenesis of alcohol-induced liver injury. The clinical relevance of the STAT5-ACSL1 pathway was examined using liver tissues from patients with alcoholic hepatitis (AH) and normal subjects (Normal). We found that chronic alcohol consumption reduced hepatic ACSL1 expression in AH patients and ALD mice. Hepatocyte-specific ACSL1 deletion exacerbated alcohol-induced liver injury by increasing free fatty acids (FFA) accumulation and cell death. Cell studies revealed that FFA elicited the translocation of BAX and p-MLKL to the lysosomal membrane, resulting in lysosomal membrane permeabilization (LMP) and thereby initiating lysosomal-mediated cell death pathway. Furthermore, we identified that the signal transducer and activator of transcription 5 (STAT5) is a novel transcriptional regulator of ACSL1. Deletion of STAT5 exacerbated alcohol-induced liver injury in association with downregulation of ACSL1, and reactivation of ACSL1 by STAT5 overexpression effectively ameliorated alcohol-induced liver injury. In addition, ACSL1 expression was positively correlated with STAT5 and negatively correlated with cell death was also validated in the liver of AH patients. ACSL1 deficiency due to STAT5 inactivation critically mediates alcohol-induced lipotoxicity and cell death in the development of ALD. These findings provide insights into alcohol-induced liver injury. [Display omitted] •ACSL1 deficiency sensitizes hepatocytes to cell death in ALD mice.•BAX binding with p-MLKL mediates lysosomal membrane permeabilization.•STAT5 is a new transcriptional regulator of ACSL1.•STAT5-ACSL1 signaling protects hepatocytes from alcohol-induced liver injury.