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

被引:15
作者
Cordoba-Chacon, Jose [1 ]
Sarmento-Cabral, Andre [1 ,2 ]
del Rio-Moreno, Mercedes [3 ]
Diaz-Ruiz, Alberto [4 ,5 ]
Subbaiah, Papasani, V [1 ,2 ]
Kineman, Rhonda D. [1 ,2 ]
机构
[1] Univ Illinois, Dept Med, Sect Endocrinol Diabet & Metab, Chicago, IL 60612 USA
[2] Jesse Brown Vet Affairs Med Ctr, Res & Dev Div, 820 South Damen Ave,Bldg 11A,Suite 6215,MP151, Chicago, IL 60612 USA
[3] Univ Cordoba, Maimonides Inst Biomed Res Cordoba IMIBIC, E-14004 Cordoba, Spain
[4] NIA, Expt Gerontol Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA
[5] Inst IMDEA Food, Nutr Intervent Grp, Precis Nutr & Aging, Madrid 28049, Spain
基金
美国国家卫生研究院;
关键词
FATTY LIVER-DISEASE; DE-NOVO LIPOGENESIS; HIV-INFECTED PATIENTS; HUMAN GROWTH-HORMONE; RECEPTOR ANTAGONIST; INSULIN-RESISTANCE; BODY-COMPOSITION; ENDOGENOUS GH; IGF-I; EXPRESSION;
D O I
10.1210/en.2018-00669
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:3761 / 3774
页数:14
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