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

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Date

2018-10-01

Authors

Cordoba-Chacon, Jose
Sarmento-Cabral, Andre
Del Rio-Moreno, Mercedes
Diaz-Ruiz, Alberto
Subbaiah, Papasani V
Kineman, Rhonda D

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Oxford University Press
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Abstract

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.

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MeSH Terms

Adipose tissue, white
Alanine transaminase
Animals
Disease models, animal
Gene knockdown techniques
Growth hormone
Hepatocytes
Lipid metabolism
Lipogenesis
Lipolysis
Liver
Liver cirrhosis
Male
Mice
Non-alcoholic fatty liver disease
Receptors, somatotropin

DeCS Terms

Alanina transaminasa
Cirrosis hepática
Enfermedad del hígado graso no alcohólico
Hormona del crecimiento
Metabolismo de los lípidos Modelos animales de enfermedad Receptores de somatotropina Técnicas de silenciamiento del gen
Modelos animales de enfermedad
Receptores de somatotropina
Técnicas de silenciamiento del gen

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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