Abstract
IL11 is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the stroma in liver disease is unclear. Here, we investigate the role of IL11 in hepatocyte lipotoxicity. Hepatocytes highly express IL11RA and secrete IL11 in response to lipid loading. Autocrine IL11 activity causes hepatocyte death through NOX4-derived ROS, activation of ERK, JNK and caspase-3, impaired mitochondrial function and reduced fatty acid oxidation. Paracrine IL11 activity stimulates hepatic stellate cells and causes fibrosis. In mouse models of NASH, hepatocyte-specific deletion of Il11ra1 protects against liver steatosis, fibrosis and inflammation while reducing serum glucose, cholesterol and triglyceride levels and limiting obesity. In mice deleted for Il11ra1, restoration of IL11 cis-signaling in hepatocytes reconstitutes steatosis and inflammation but not fibrosis. We found no evidence for the existence of IL6 or IL11 trans-signaling in hepatocytes or NASH. These data show that IL11 modulates hepatocyte metabolism and suggests a mechanism for NAFLD to NASH transition.
Highlights
Interleukin 11 (IL11) is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the stroma in liver disease is unclear
We used a range of in vitro and in vivo approaches to address key questions regarding IL11 in hepatocyte biology, nonalcoholic fatty liver disease (NAFLD), and NASH: (1) Defining the role of IL11 signaling in human hepatocytes, (2) examining whether lipotoxicity is related to IL11 activity in hepatocytes, (3) establishing whether IL11 trans-signaling contributes to NASH, (4) dissecting the interrelationship between IL11 cis-signaling in hepatocytes and the development of steatosis, hepatocyte death, inflammation, and fibrosis
As compared to control livers, IL11RA expression was increased in liver biopsies from patients with NASH and in livers from mice with NASH on a Western Diet supplemented with fructose (Supplementary Fig. 2b and c)
Summary
IL11 is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the stroma in liver disease is unclear. We used a range of in vitro and in vivo approaches to address key questions regarding IL11 in hepatocyte biology, NAFLD, and NASH: (1) Defining the role of IL11 signaling in human hepatocytes, (2) examining whether lipotoxicity is related to IL11 activity in hepatocytes, (3) establishing whether IL11 (or IL6) trans-signaling contributes to NASH, (4) dissecting the interrelationship between IL11 cis-signaling in hepatocytes and the development of steatosis, hepatocyte death, inflammation, and fibrosis. These studies demonstrate a detrimental effect of lipotoxicity-associated IL11 signaling in hepatocytes that appears to be apical pathology in the aetiology of NASH
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