Abstract:
BACKGROUND:Non-alcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver diseases closely associated with obesity and insulin resistance; deficient growth hormone (GH) action in liver has been implicated as a mechanism. Here, we investigated the evolution of NAFLD in aged mice with liver-specific GHR deletion. METHODS:We examined glucose tolerance, insulin responsiveness, and lipid profiles in aged male mice (44-50 weeks) with GHRLD. We performed proteomics analysis, pathway-based Superarray assay, as well as quantitative RT-PCR to gain molecular insight into the mechanism(s) of GHR-deficiency-mediated NAFLD. In addition, we examined the pathological changes of livers of aged GHRLD male mice. RESULTS:The biochemical profile was consistent with that of the metabolic syndrome: abnormal glucose tolerance, impaired insulin secretion, and hyperlipidemia. RT-qPCR analysis of key markers of inflammation revealed a three- to fivefold increase in TNFα and CCL3, confirming the presence of inflammation. Expression of fibrotic markers (e.g., Col1A2 and Col3A1) was significantly increased, together with a two- to threefold increase in TGFβ transcripts. Proteomics analyses showed a marked decrease of Mup1 and Selenbp2. In addition, pathway-analysis showed that the expression of cell cycle and growth relevant genes (i.e., Ccnd1, Socs2, Socs3, and Egfr) were markedly affected in GHRLD liver. Microscopic analyses (H&E) of GHRLD livers revealed the presence of hepatic adenomas of different stages of malignancy. CONCLUSION:Abrogation of GH signaling in male liver leads to metabolic syndrome, hepatic steatosis, increased inflammation and fibrosis, and development of hepatic tumor. Since obesity, a common precursor of NAFLD, is a state of deficient GH secretion and action, the GHRLD model could be used to unravel the contribution of compromised hepatic GH signaling in these pathological processes, and help to identify potential targets for intervention.
journal_name
Front Endocrinol (Lausanne)journal_title
Frontiers in endocrinologyauthors
Fan Y,Fang X,Tajima A,Geng X,Ranganathan S,Dong H,Trucco M,Sperling MAdoi
10.3389/fendo.2014.00218subject
Has Abstractpub_date
2014-12-18 00:00:00pages
218issn
1664-2392journal_volume
5pub_type
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