The hepatic integrated stress response suppresses the somatotroph axis to control liver damage in nonalcoholic fatty liver disease

Rika Ohkubo; Wei-Chieh Mu; Chih-Ling Wang; Zehan Song; Marine Barthez; Yifei Wang; Nathaniel Mitchener; Rasul Abdullayev; Yeong Rim Lee; Yuze Ma; Megan Curtin; Suraj Srinivasan; Xingjia Zhang; Fanghan Yang; Peter H Sudmant; Angela Oliveira Pisco; Norma Neff; Cole M Haynes; Danica Chen

doi:10.1016/j.celrep.2022.111803

The hepatic integrated stress response suppresses the somatotroph axis to control liver damage in nonalcoholic fatty liver disease

Cell Rep. 2022 Dec 13;41(11):111803. doi: 10.1016/j.celrep.2022.111803.

Authors

Rika Ohkubo¹, Wei-Chieh Mu², Chih-Ling Wang³, Zehan Song¹, Marine Barthez³, Yifei Wang¹, Nathaniel Mitchener³, Rasul Abdullayev³, Yeong Rim Lee², Yuze Ma³, Megan Curtin³, Suraj Srinivasan³, Xingjia Zhang³, Fanghan Yang², Peter H Sudmant⁴, Angela Oliveira Pisco⁵, Norma Neff⁵, Cole M Haynes⁶, Danica Chen⁷

Affiliations

¹ Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
² Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA.
³ Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁴ Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁵ Chan Zuckerberg Biohub, San Francisco, CA, USA.
⁶ Department of Molecular, Cell and Cancer Biology, UMass-Chan Medical School, Worcester, MA 01605, USA.
⁷ Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: danicac@berkeley.edu.

Abstract

Nonalcoholic fatty liver disease (NAFLD) can be ameliorated by calorie restriction, which leads to the suppressed somatotroph axis. Paradoxically, the suppressed somatotroph axis is associated with patients with NAFLD and is correlated with the severity of fibrosis. How the somatotroph axis becomes dysregulated and whether the repressed somatotroph axis impacts liver damage during the progression of NAFLD are unclear. Here, we identify a regulatory branch of the hepatic integrated stress response (ISR), which represses the somatotroph axis in hepatocytes through ATF3, resulting in enhanced cell survival and reduced cell proliferation. In mouse models of NAFLD, the ISR represses the somatotroph axis, leading to reduced apoptosis and inflammation but decreased hepatocyte proliferation and exacerbated fibrosis in the liver. NAD⁺ repletion reduces the ISR, rescues the dysregulated somatotroph axis, and alleviates NAFLD. These results establish that the hepatic ISR suppresses the somatotroph axis to control cell fate decisions and liver damage in NAFLD.

Keywords: ATF3; CP: Metabolism; ER stress; IGF-1; SIRT7; aging; integrated stress response; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; sirtuin; somatotroph axis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Hepatocytes / pathology
Liver / pathology
Liver Cirrhosis / pathology
Mice
Non-alcoholic Fatty Liver Disease* / pathology
Somatotrophs*

Abstract

Publication types

MeSH terms

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