Adult-Onset Hepatocyte GH Resistance Promotes NASH in Male Mice, Without Severe Systemic Metabolic Dysfunction.

Cordoba-Chacon, JoseSarmento-Cabral, AndreDel Rio-Moreno, MercedesDiaz-Ruiz, AlbertoSubbaiah, Papasani VKineman, Rhonda D2023-01-252023-01-252018-10-01Cordoba-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):3761-3774http://hdl.handle.net/10668/13040Nonalcoholic 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.enAdipose tissue, whiteAlanine transaminaseAnimalsDisease models, animalGene knockdown techniquesGrowth hormoneHepatocytesLipid metabolismLipogenesisLipolysisLiverLiver cirrhosisMaleMiceNon-alcoholic fatty liver diseaseReceptors, somatotropinAdult-Onset Hepatocyte GH Resistance Promotes NASH in Male Mice, Without Severe Systemic Metabolic Dysfunction.Research article30295789open accessAlanina transaminasaCirrosis hepáticaEnfermedad del hígado graso no alcohólicoHormona del crecimientoMetabolismo de los lípidos Modelos animales de enfermedad Receptores de somatotropina Técnicas de silenciamiento del genModelos animales de enfermedadReceptores de somatotropinaTécnicas de silenciamiento del gen10.1210/en.2018-006691945-7170PMC6202859https://academic.oup.com/endo/article-pdf/159/11/3761/26180602/en.2018-00669.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202859/pdf