Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41467-020-20303-z
Title: Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH
Authors: Dong, Jinrui 
Viswanathan, Sivakumar 
Adami, Eleonora 
Singh, Brijesh K 
Chothani, Sonia P 
Ng, Benjamin
Lim, Wei Wen 
Zhou, Jin 
Tripathi, Madhulika 
Ko, Nicole SJ
Shekeran, Shamini G
Tan, Jessie 
Lim, Sze Yun 
Wang, Mao
Lio, Pei Min
Yen, Paul M 
Schafer, Sebastian 
Cook, Stuart A 
Widjaja, Anissa A 
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
LIVER-INJURY
INTERLEUKIN-11
MECHANISMS
STEATOSIS
FIBROSIS
PATHWAY
STRESS
Issue Date: 4-Jan-2021
Publisher: NATURE RESEARCH
Citation: Dong, Jinrui, Viswanathan, Sivakumar, Adami, Eleonora, Singh, Brijesh K, Chothani, Sonia P, Ng, Benjamin, Lim, Wei Wen, Zhou, Jin, Tripathi, Madhulika, Ko, Nicole SJ, Shekeran, Shamini G, Tan, Jessie, Lim, Sze Yun, Wang, Mao, Lio, Pei Min, Yen, Paul M, Schafer, Sebastian, Cook, Stuart A, Widjaja, Anissa A (2021-01-04). Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH. NATURE COMMUNICATIONS 12 (1). ScholarBank@NUS Repository. https://doi.org/10.1038/s41467-020-20303-z
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.
Source Title: NATURE COMMUNICATIONS
URI: https://scholarbank.nus.edu.sg/handle/10635/226687
ISSN: 20411723
DOI: 10.1038/s41467-020-20303-z
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