Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and may progress to non-alcoholic steatohepatitis (NASH) and liver fibrosis. The deficit of pharmacological therapies for the latter mainly results from an incomplete understanding of involved pathological mechanisms. Herein, we identify apoptosis signal-regulating kinase 1 (ASK1) as a suppressor of NASH and fibrosis formation. High-fat diet-fed and aged chow-fed liver-specific ASK1-knockout mice develop a higher degree of hepatic steatosis, inflammation, and fibrosis compared to controls. In addition, pharmacological inhibition of ASK1 increased hepatic lipid accumulation in wild-type mice. In line, liver-specific ASK1 overexpression protected mice from the development of high-fat diet-induced hepatic steatosis and carbon tetrachloride-induced fibrosis. Mechanistically, ASK1 depletion blunts autophagy, thereby enhancing lipid droplet accumulation and liver fibrosis. In human livers of lean and obese subjects, ASK1 expression correlated negatively with liver fat content and NASH scores, but positively with markers for autophagy. Taken together, ASK1 may be a novel therapeutic target to tackle NAFLD and liver fibrosis.

中文翻译：

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肝脏 ASK1 可预防非酒精性脂肪肝疾病和纤维化。

非酒精性脂肪肝病（NAFLD）与肥胖密切相关，并可能进展为非酒精性脂肪性肝炎（NASH）和肝纤维化。后者的药物治疗的缺陷主要是由于对所涉及的病理机制的不完全理解造成的。在此，我们确定凋亡信号调节激酶 1 (ASK1) 是 NASH 和纤维化形成的抑制剂。与对照组相比，高脂肪饮食喂养和老年饲料喂养的肝脏特异性 ASK1 基因敲除小鼠会出现更严重的肝脏脂肪变性、炎症和纤维化。此外，ASK1 的药理抑制会增加野生型小鼠的肝脏脂质积累。与此一致的是，肝脏特异性 ASK1 过度表达可以保护小鼠免受高脂肪饮食诱导的肝脂肪变性和四氯化碳诱导的纤维化的发展。从机制上讲，ASK1 耗竭会减弱自噬，从而增强脂滴积累和肝纤维化。在瘦和肥胖受试者的人类肝脏中，ASK1 表达与肝脏脂肪含量和 NASH 评分呈负相关，但与自噬标记物呈正相关。总而言之，ASK1 可能是解决 NAFLD 和肝纤维化的新治疗靶点。