Exploring the molecular mechanisms underlying the potentiation of exogenous growth hormone on alcohol-induced fatty liver diseases in mice

Background: Growth hormone (GH) is an essential regulator of intrahepatic lipid metabolism by activating multiple complex hepatic signaling cascades. Here, we examined whether chronic exogenous GH administration (via gene therapy) could ameliorate liver steatosis in animal models of alcoholic fatty liver disease (AFLD) and explored the underlying molecular mechanisms. Methods: Male C57BL/6J mice were fed either an alcohol or a control liquid diet with or without GH therapy for 6 weeks. Biochemical parameters, liver histology, oxidative stress markers, and serum high molecular weight (HMW) adiponectin were measured. Quantitative real-time PCR and western blotting were also conducted to determine the underlying molecular mechanism. Results: Serum HMW adiponectin levels were significantly higher in the GH1-treated control group than in the control group (3.98 +/- 0.71 mu g/mL vs. 3.07 +/- 0.55 mu g/mL; P < 0.001). GH1 therapy reversed HMW adiponectin levels to the normal levels in the alcohol-fed group. Alcohol feeding significantly reduced hepatic adipoR2 mRNA expression compared with that in the control group (0.71 +/- 0.17 vs. 1.03 +/- 0.19; P < 0.001), which was reversed by GH therapy. GH1 therapy also significantly increased the relative mRNA (1.98 +/- 0.15 vs. 0.98 +/- 0.15) and protein levels of SIRT1 (2.18 +/- 0.37 vs. 0.99 +/- 0.17) in the alcohol-fed group compared with those in the control group (both, P < 0.001). The alcohol diet decreased the phosphorylated and total protein levels of hepatic AMP-activated kinase-alpha (AMPK alpha) (phosphorylated protein: 0.40 +/- 0.14 vs. 1.00 +/- 0.12; total protein: 0.32 +/- 0.12 vs. 1.00 +/- 0.14; both, P < 0.001) and peroxisome proliferator activated receptor-alpha (PPAR alpha) (phosphorylated protein: 0.30 +/- 0.09 vs. 1.00 +/- 0.09; total protein: 0.27 +/- 0.10 vs. 1.00 +/- 0.13; both, P < 0.001), which were restored by GH1 therapy. GH therapy also decreased the severity of fatty liver in alcohol-fed mice. Conclusions: GH therapy had positive effects on AFLD and may offer a promising approach to prevent or treat AFLD. These beneficial effects of GH on AFLD were achieved through the activation of the hepatic adiponectin-SIRT1-AMPK and PPAR alpha-AMPK signaling systems.