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GH directly inhibits steatosis and liver injury in a sex-dependent and IGF1-independent manner.
Sarmento-Cabral, Andre; Del Rio-Moreno, Mercedes; Vazquez-Borrego, Mari C; Mahmood, Mariyah; Gutierrez-Casado, Elena; Pelke, Natalie; Guzman, Grace; Subbaiah, Papasani V; Cordoba-Chacon, Jose; Yakar, Shoshana; Kineman, Rhonda D.
Afiliación
  • Sarmento-Cabral A; 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.
  • Del Rio-Moreno M; 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.
  • Vazquez-Borrego MC; 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.
  • Mahmood M; 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.
  • Gutierrez-Casado E; 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.
  • Pelke N; 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.
  • Guzman G; Department of Pathology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois, USA.
  • Subbaiah PV; 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.
  • Cordoba-Chacon J; 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.
  • Yakar S; Department of Molecular Pathobiology, New York University College of Dentistry, New York, New York, USA.
  • Kineman RD; 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.
J Endocrinol ; 248(1): 31-44, 2021 01.
Article en En | MEDLINE | ID: mdl-33112796
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor I del Crecimiento Similar a la Insulina / Hormona del Crecimiento / Hepatocitos / Hígado Graso / Hígado Límite: Animals Idioma: En Revista: J Endocrinol Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor I del Crecimiento Similar a la Insulina / Hormona del Crecimiento / Hepatocitos / Hígado Graso / Hígado Límite: Animals Idioma: En Revista: J Endocrinol Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido