Autocrine IL11 cis-signaling in hepatocytes is an initiating nexus between lipotoxicity and non-alcoholic steatohepatitis

Dong, J.; Adami, E.; Chothani, S.; Viswanathan, S.; NG, B.; Lim, W.-W.; Singh, B. K.; Zhou, J.; Ko, N.; Shekeran, S. G.; Tan, J.; Lim, S. Y.; Wang, M.; Lio, P. M.; Yen, P. M.; Schafer, S.; Cook, S. A.; Widjaja, A. A.

doi:10.1101/2020.03.11.986802

bioRxiv · 10.1101/2020.03.11.986802

Autocrine IL11 cis-signaling in hepatocytes is an initiating nexus between lipotoxicity and non-alcoholic steatohepatitis

Dong, J.·Adami, E.·Chothani, S.·Viswanathan, S.·NG, B.·Lim, W.-W.·Singh, B. K.·Zhou, J.·Ko, N.·Shekeran, S. G.·Tan, J.·Lim, S. Y.·Wang, M.·Lio, P. M.·Yen, P. M.·Schafer, S.·Cook, S. A.·Widjaja, A. A.

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Abstract

Background and aimsIL11 signaling is important in non-alcoholic steatohepatitis (NASH) but how it contributes to NASH pathologies beyond fibrosis is not known. Here we investigate the role of IL11 signaling in hepatocyte lipotoxicity. MethodsHepatocytes were stimulated with IL6, IL11, HyperIL6, or HyperIL11 alone or in the presence of soluble gp130 (sgp130) or soluble IL11RA (sIL11RA), or loaded with palmitate in the presence of IgG or anti-IL11RA (X209) antibodies or sgp130. Effects were assessed using colorimetric ALT, GSH, or ELISA assays, immunoblots, and flow cytometry. The relative contributions of IL11 cis-versus -trans signaling in vivo was assessed in two preclinical NASH models using a high fat methionine/choline deficient diet or a Western diet with liquid fructose in C57BL6/Ntac mice injected with AAV8-Alb-Cre, AAV8-Alb-sgp130, in mice with hepatocyte-specific deletion of Il11ra (CKO), and in mice with global deletion of Il11ra injected with AAV8-Alb-mIl11ra or AAV8-Alb-sIl11ra. Livers and serum were collected; serum samples were analyzed using biochemistry and liver tissues were analyzed by histology, qPCR, immunobloting, hydroxyproline, and GSH assays. ResultsWe show that lipid-laden hepatocytes secrete IL11, which acts via autocrine cis-signaling to cause lipoapoptosis. IL11 causes lipotoxic hepatocyte death through activation of non-canonical signaling pathways and increased NOX4-derived reactive oxygen species. In two preclinical models, hepatocyte-specific deletion of Il11ra1 protects mice from all aspects of NASH with beneficial effects on body weight. In accordance, restoration of IL11 cis-signaling in hepatocytes only in mice globally deleted for Il11ra1 reconstitutes steatosis and inflammation. Throughout, we found no evidence to support the existence of IL6 or IL11 trans-signaling in the liver. ConclusionWe conclude that autocrine IL11-mediated cell death underlies hepatocyte lipotoxicity and that liver fibrosis and inflammation occur subsequently. These data highlight a new disease mechanism for the transition from compensated fatty liver disease to NASH.

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Dong, J., Adami, E., Chothani, S., Viswanathan, S., NG, B., Lim, W.-W., Singh, B. K., Zhou, J., Ko, N., Shekeran, S. G., Tan, J., Lim, S. Y., Wang, M., Lio, P. M., Yen, P. M., Schafer, S., Cook, S. A., Widjaja, A. A.. 2020-03-12. Autocrine IL11 cis-signaling in hepatocytes is an initiating nexus between lipotoxicity and non-alcoholic steatohepatitis. https://doi.org/10.1101/2020.03.11.986802

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