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

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. [Display omitted] •Hepatic ER stress suppresses the somatotroph axis by inducing ATF3•Suppression of the somatotroph axis controls liver damage in NAFLD•NAD+ repletion ameliorates dysregulated somatotroph axis and liver damage in NAFLD Ohkubo et al. show that hepatic ER stress results in the suppression of the somatotroph axis, which controls liver damage in nonalcoholic fatty liver disease by preventing hepatocyte death and proliferation, resulting in reduced inflammation but increased fibrosis. This study has important implications in treating this prevalent metabolic disease.