IGF-1-Independent Actions of Liver Growth Hormone Receptor in Male Mice

Presentation Number: OR40-2
Date of Presentation: April 4th, 2016

Zhongbo Liu*1, Bruce Cronstein2, Hailing Liu2, Radhika H Muzumdar3, Zhenwei Gong3, Haim Werner4 and Shoshana Yakar1
1New York University College of Dentistry, New York, NY, 2New York University, 3Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 4Tel Aviv University, Tel Aviv, Israel

Abstract

Apart from stimulating growth, the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis has direct effects on fuel metabolism. The GH receptor (GHR) is found on hepatocytes, myocytes, and adipocytes, and mediates glucose, amino acids and lipid metabolism. IGF-1 has insulin-like effects, and when given acutely it enhances glucose uptake by muscle. In mice, liver-specific deletion of GHR (Li-GHRKO) resulted in marked decrease in serum IGF-1 levels (~95%), significant increases in fat mass (~1.9 fold) and serum lipids (~1.4 fold), and severe hepatic steatosis. Likewise, liver-specific disruption of the GHR mediators, JAK2 or STAT5, resulted in dyslipidemia and hepatic steatosis. In contrast, liver IGF-1 deficient mice (LID) with 75% reductions in serum IGF-1 do not develop hepatic steatosis. Our goal in this study was threefold: 1) to address the roles of liver-derived IGF-1 in the development of hepatic steatosis induced by GH resistance, 2) to determine the roles of liver-derived IGF-1 in the development of steatosis-induced hepatic inflammation, and 3) to establish correlations between liver-derived IGF-1 and levels of oxidative stress markers in serum, liver, and muscle. To that end we generated a new mouse model, with liver-specific GHRKO that express hepatic IGF-1 transgene (HIT), namely Li-GHRKO-HIT. We found that restoration of hepatic IGF-1 in the Li-GHRKO mice rescued body composition improved glucose homeostasis, but was insufficient to restore the impaired liver lipid metabolism. Hepatic-IGF-1 reduced lipid and protein oxidation in the Li-GHRKO mice, but did not resolve steatosis-induced inflammation. We conclude that GH regulates liver de novo lipogenesis in an IGF-1 independent manner and plays significant roles in steatosis-induced hepatic inflammation.

 

Nothing to Disclose: ZL, BC, HL, RHM, ZG, HW, SY