Abstract
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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease affecting up to 40% of adults and children (Imajo et al, 2012; Koyama & Brenner, 2017; Friedman et al, 2018)
The spectrum of NAFLD ranges from simple hepatic lipid accumulation to non-alcoholic steatohepatitis (NASH), which can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma (Imajo et al, 2012; Meex et al, 2015; Zhang et al, 2016b)
The present study uncovers a protective role of liver-expressed apoptosis signal-regulating kinase 1 (ASK1) in the development of NAFLD and liver fibrosis. Such notion is supported by the fact that genetic depletion and pharmacological inhibition of ASK1 in vivo and in vitro increased hepatic lipid droplet accumulation and/or liver fibrosis, potentially via blocking autophagy function
Summary
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease affecting up to 40% of adults and children (Imajo et al, 2012; Koyama & Brenner, 2017; Friedman et al, 2018). Increased uptake of free fatty acids (FFA), elevated de novo lipogenesis, decreased fat oxidation, reduced hepatic very low-density lipoprotein (VLDL) secretion, and impaired autophagy may contribute to the development of hepatic steatosis (Kohjima et al, 2007; Benhamed et al, 2012; Hur et al, 2016). The latter is induced during nutrient deprivation or stress conditions to maintain cellular homeostasis (Wang, 2015). Activation of autophagy promotes anti-inflammatory pathways (Lodder et al, 2015), and impaired autophagy induces steatosis and liver fibrosis (Yang et al, 2010; GonzalezRodriguez et al, 2014; Inokuchi-Shimizu et al, 2014; Stienstra et al, 2014; Lodder et al, 2015)
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