GH directly inhibits steatosis and liver injury in a sex-dependent and IGF1-independent manner

Andre Sarmento-Cabral, Mercedes Del Rio-Moreno, Mari C. Vazquez-Borrego, Mariyah Mahmood, Elena Gutierrez-Casado, Natalie Pelke, Grace Guzman, Papasani V. Subbaiah, Jose Cordoba-Chacon, Shoshana Yakar, Rhonda D. Kineman

Research output: Contribution to journalArticlepeer-review

Abstract

A reduction in hepatocyte growth hormone (GH)-signaling promotes non-alcoholic fatty liver disease (NAFLD). However, debate remains as to the relative contribution of the direct effects of GH on hepatocyte function vs indirect e ffects, via alterations in insulin-like growth factor 1 (IGF1). To isolate the role of hepatocyte GH receptor (GHR) signaling, independent of changes in IGF1, mice with adult-onset, hepatocyte-specific GHR knockdown (aHepGHRkd) were treated with a vector ex pressing rat IGF1 targeted specifically to hepatocytes. Compared to GHR-intact mic e, aHepGHRkd reduced circulating IGF1 and elevated GH. In male aHepGHRkd, the shift in IGF1/GH did not alter plasma glucose or non-esterified fatty acids (NEFA), but was ass ociated with increased insulin, enhanced systemic lipid oxidation and reduced white ad ipose tissue (WAT) mass. Livers of male aHepGHRkd exhibited steatosis associated w ith increased de novo lipogenesis, hepatocyte ballooning and inflammation. In female a HepGHRkd, hepatic GHR protein levels were not detectable, but moderate levels of IGF1 were maintained, with minimal alterations in systemic metabolism and no evidence of steatosis. Reconstitution of hepatocyte IGF1 in male aHepGHRkd lowered GH and normalized insulin, whole body lipid utilization and WAT mass. However, IG F1 reconstitution did not reduce steatosis or eliminate liver injury. RNAseq analysis showed IGF1 reconstitution did not impact aHepGHRkd-induced changes in liver gene expressi on, despite changes in systemic metabolism. These results demonstrate the impact of aH epGHRkd is sexually dimorphic and the steatosis and liver injury observed in male aHepGHRkd mice is autonomous of IGF1, suggesting GH acts directly on the adult hepatocyte to control NAFLD progression.

Original languageEnglish (US)
Pages (from-to)31-44
Number of pages14
JournalJournal of Endocrinology
Volume248
Issue number1
DOIs
StatePublished - Jan 2021

Keywords

  • Growth hormone
  • IGF1
  • Liver
  • Non-alcoholic fatty liver disease

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Fingerprint Dive into the research topics of 'GH directly inhibits steatosis and liver injury in a sex-dependent and IGF1-independent manner'. Together they form a unique fingerprint.

Cite this