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

in Journal of Endocrinology
Authors:
Andre Sarmento-Cabral Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA

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Mercedes del Rio-Moreno Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA

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Mari C Vazquez-Borrego Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA

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Mariyah Mahmood Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA

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Elena Gutierrez-Casado Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA

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Natalie Pelke Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA

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Grace Guzman Department of Pathology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois, USA

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Papasani V Subbaiah Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA

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Jose Cordoba-Chacon Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA

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Shoshana Yakar Department of Molecular Pathobiology, New York University College of Dentistry, New York, New York, USA

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Rhonda D Kineman Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA

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Correspondence should be addressed to A Sarmento-Cabral or R D Kineman: amsbcabral@gmail.com or kineman@uic.edu
DOI:
https://doi.org/10.1530/JOE-20-0326
Volume/Issue:
Volume 248: Issue 1
Article Type:
Research Article
Page Range:
31–44
Online Publication Date:
Jan 2021
Copyright:
© 2021 Society for Endocrinology 2021
Collections:
Top-cited articles of 2023
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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 effects, 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 expressing rat IGF1 targeted specifically to hepatocytes. Compared to GHR-intact mice, 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 associated with increased insulin, enhanced systemic lipid oxidation and reduced white adipose tissue (WAT) mass. Livers of male aHepGHRkd exhibited steatosis associated with increased de novo lipogenesis, hepatocyte ballooning and inflammation. In female aHepGHRkd, 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, IGF1 reconstitution did not reduce steatosis or eliminate liver injury. RNAseq analysis showed IGF1 reconstitution did not impact aHepGHRkd-induced changes in liver gene expression, despite changes in systemic metabolism. These results demonstrate the impact of aHepGHRkd 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.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2021 Society for Endocrinology 2021
Page(s):
14
Article Type:
Research Article
Received Date:
25 Sep 2020
Accepted Date:
20 Oct 2020
Print Publication Date:
01 Jan 2021
Online Publication Date:
Jan 2021
Keywords:
growth hormone; non-alcoholic fatty liver disease; IGF1; liver

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