RT Journal Article
T1 Adult-Onset Hepatocyte GH Resistance Promotes NASH in Male Mice, Without Severe Systemic Metabolic Dysfunction.
A1 Cordoba-Chacon, Jose
A1 Sarmento-Cabral, Andre
A1 Del Rio-Moreno, Mercedes
A1 Diaz-Ruiz, Alberto
A1 Subbaiah, Papasani V
A1 Kineman, Rhonda D
AB Nonalcoholic fatty liver disease (NAFLD), which includes nonalcoholic steatohepatitis (NASH), is associated with reduced GH input/signaling, and GH therapy is effective in the reduction/resolution of NAFLD/NASH in selected patient populations. Our laboratory has focused on isolating the direct vs indirect effects of GH in preventing NAFLD/NASH. We reported that chow-fed, adult-onset, hepatocyte-specific, GH receptor knockdown (aHepGHRkd) mice rapidly (within 7 days) develop steatosis associated with increased hepatic de novo lipogenesis (DNL), independent of changes in systemic metabolic function. In this study, we report that 6 months after induction of aHepGHRkd early signs of NASH develop, which include hepatocyte ballooning, inflammation, signs of mild fibrosis, and elevated plasma alanine aminotransferase. These changes occur in the presence of enhanced systemic lipid utilization, without evidence of white adipose tissue lipolysis, indicating that the liver injury that develops after aHepGHRkd is due to hepatocyte-specific loss of GH signaling and not due to secondary defects in systemic metabolic function. Specifically, enhanced hepatic DNL is sustained with age in aHepGHRkd mice, associated with increased hepatic markers of lipid uptake/re-esterification. Because hepatic DNL is a hallmark of NAFLD/NASH, these studies suggest that enhancing hepatocyte GH signaling could represent an effective therapeutic target to reduce DNL and treat NASH.
PB Oxford University Press
YR 2018
FD 2018-10-01
LK http://hdl.handle.net/10668/13040
UL http://hdl.handle.net/10668/13040
LA en
NO Cordoba-Chacon J, Sarmento-Cabral A, Del Rio-Moreno M, Diaz-Ruiz A, Subbaiah PV, Kineman RD. Adult-Onset Hepatocyte GH Resistance Promotes NASH in Male Mice, Without Severe Systemic Metabolic Dysfunction. Endocrinology. 2018 Nov 1;159(11):3761-3774
NO We thank Neena Majumdar for breeding the Ghrfl/fl mice and assisting in the analysis of samples/mice; Dr. Rafael de Cabo (Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD) for assistance in the protein analysis of the aHepGHRkd livers; Dr. John J. Kopchick (Edison iotechnology Institute and Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH) for providing the Ghrfl/fl mouse model; and Dr. Natalia Nieto (University of Illinois at Chicago, Chicago, IL) for key discussions of the hepatic pathophysiology of aHepGHRkdmice. Part of this work was presented at the 2017 and 2018 Endocrine Society’s Annual meetings in Orlando, FL, and Chi cago, IL, respectively.Financial Support: This work was supported by National Institutes of Health Grant K01DK115525 (to J.C.-C.); the Intramural Research Program of the National Institutes of Health, National Institute on Aging (to A.D.-R.); US Department of Veterans Affairs, Office of Research and Development MeritAward BX001090 (to P.V.S.); National Institutes of Health Grants R21AT008457 and S10OD010660 (to P.V.S); and by US Department of Veterans Affairs, Office of Research and Development Merit Award BX001114 (to R.D.K.).
DS RISalud
RD Apr 9, 2025