| Literature DB >> 33397952 |
Jinrui Dong1, Sivakumar Viswanathan1, Eleonora Adami1, Brijesh K Singh1, Sonia P Chothani1, Benjamin Ng1,2, Wei Wen Lim2, Jin Zhou1, Madhulika Tripathi1, Nicole S J Ko1, Shamini G Shekeran1, Jessie Tan1,2, Sze Yun Lim2, Mao Wang1, Pei Min Lio2, Paul M Yen1, Sebastian Schafer1,2, Stuart A Cook3,4,5,6, Anissa A Widjaja7.
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.Entities:
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Year: 2021 PMID： 33397952 PMCID： PMC7782504 DOI： 10.1038/s41467-020-20303-z
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919