Fatty Liver and the Osseous System; Lessons from Male Mice with Liver Specific Ghr Ablation and Non-Alcoholic Fatty Liver Disease

Presentation Number: MON 329
Date of Presentation: April 3rd, 2017

Zhongbo Liu1, Tiazhen Han2, Mitchell B Schaffler3 and Shoshana Yakar*4
1New York University College of Dentistry, NY, NY, 2New York University College of Dentistry New York, NY, NY, 3City College of New York, New York, 4New York University COLLEGE OF D, New York, NY


Hepatic osteodystrophy refers to bone loss associated with liver disease. Non-alcoholic fatty liver disease (NAFLD) affects almost 30% of the population and is considered one of the manifestations of the metabolic-syndrome endemic. Clinical studies have demonstrated poor bone health in both children and adults with NAFLD. NAFLD associates with reductions in serum insulin-like growth factor-1 (IGF-1), an established regulator of bone acquisition during growth. Growth hormone (GH) resistance due to liver specific ablation of the GHR (Li-GHRKO), results in NAFLD, systemic dyslipidemia, reductions in serum IGF-1, and severe osteopenia. Since GH tightly regulates hepatic production of IGF-1, target ablation of GHR in liver significantly decreases serum IGF-1 and thus leaving the following questions unanswered: 1) does osteopenia in GH resistance state caused solely by the reductions in liver production of circulating IGF-1? And 2) does hepatic GHR regulate bone metabolism via mediators other than IGF-1? To address these questions we have recently created a combined mouse model with liver GHR deletion, in which we restored IGF-1 production via hepatic IGF-1 transgene (HIT), the Li-GHRKO-HIT mouse. We show that normalized serum IGF-1 levels in the Li-GHRKO-HIT mice did NOT resolve NAFLD, or hepatic inflammation. Li-GHRKO-HIT mice showed normal cortical morphology and mechanical strength. However, despite normal serum IGF-1 levels, Li-GHRKO-HIT mice exhibited marked decrease in trabecular bone volume and density associated with increased liver production of tumor necrosis factor a (TNFa), and osteopontin (OPN), an inhibitor of mineral crystal growth. Our data is consistent with a previous report (PMID:23595986), establishing that GH directly inhibits OPN and with several reports showing that GH resistance associates with increased TNFa levels. We conclude that liver GHR activation exerts its action on bone not only via stimulating IGF-1 production in the liver, but also via inhibition of OPN and TNFa, both of which have negative effects on skeletal acquisition.


Nothing to Disclose: ZL, TH, MBS, SY