No abstract

Hepatic steatosis and insulin resistance are among the most prevalent metabolic disorders and are tightly associated with obesity and type 2 diabetes. However, the underlying mechanisms linking obesity to hepatic lipid accumulation and insulin resistance are incompletely understood. Glycoprotein 130 (gp130) is the common signal transducer of all interleukin 6 (IL-6) cytokines. We provide evidence that gp130-mediated adipose tissue lipolysis promotes hepatic steatosis and insulin resistance. In obese mice, adipocyte-specific gp130 deletion reduced basal lipolysis and enhanced insulin's ability to suppress lipolysis from mesenteric but not epididymal adipocytes. Consistently, free fatty acid levels were reduced in portal but not in systemic circulation of obese knockout mice. Of note, adipocyte-specific gp130 knockout mice were protected from high-fat diet-induced hepatic steatosis as well as from insulin resistance. In humans, omental but not subcutaneous IL-6 mRNA expression correlated positively with liver lipid accumulation (r = 0.31, P < 0.05) and negatively with hyperinsulinemic-euglycemic clamp glucose infusion rate (r = 20.28, P < 0.05). The results show that IL-6 cytokineinduced lipolysis may be restricted to mesenteric white adipose tissue and that it contributes to hepatic insulin resistance and steatosis. Therefore, blocking IL-6 cytokine signaling in (mesenteric) adipocytes may be a novel approach to blunting detrimental fat-liver crosstalk in obesity.

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.