Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH

Jinrui Dong, Sivakumar Viswanathan, Eleonora Adami, Brijesh K. Singh, Sonia P. Chothani, Benjamin Ng, Wei Wen Lim, Jin Zhou, Madhulika Tripathi, Nicole S. J. Ko, Shamini G. Shekeran, Jessie Tan, Sze Yun Lim, Mao Wang, Pei Min Lio, Paul M. Yen, Sebastian Schafer, Stuart A. Cook () and Anissa A. Widjaja ()
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Jinrui Dong: Duke-National University of Singapore Medical School
Sivakumar Viswanathan: Duke-National University of Singapore Medical School
Eleonora Adami: Duke-National University of Singapore Medical School
Brijesh K. Singh: Duke-National University of Singapore Medical School
Sonia P. Chothani: Duke-National University of Singapore Medical School
Benjamin Ng: Duke-National University of Singapore Medical School
Wei Wen Lim: National Heart Research Institute Singapore, National Heart Centre Singapore
Jin Zhou: Duke-National University of Singapore Medical School
Madhulika Tripathi: Duke-National University of Singapore Medical School
Nicole S. J. Ko: Duke-National University of Singapore Medical School
Shamini G. Shekeran: Duke-National University of Singapore Medical School
Jessie Tan: Duke-National University of Singapore Medical School
Sze Yun Lim: National Heart Research Institute Singapore, National Heart Centre Singapore
Mao Wang: Duke-National University of Singapore Medical School
Pei Min Lio: National Heart Research Institute Singapore, National Heart Centre Singapore
Paul M. Yen: Duke-National University of Singapore Medical School
Sebastian Schafer: Duke-National University of Singapore Medical School
Stuart A. Cook: Duke-National University of Singapore Medical School
Anissa A. Widjaja: Duke-National University of Singapore Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20303-z

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