Metabolomic Investigation of the Impact of Growth Hormone on Nonalcoholic Fatty Liver Disease: Identification of Novel Biomarkers and Therapeutic Targets

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PROJECT SUMMARY Nonalcoholic fatty liver disease (NAFLD) is a serious weight-related complication that is present in 80% of individuals with obesity in the United States. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, is characterized by inflammation, cell death, and fibrosis, which can lead to cirrhosis, decompensated liver disease, and hepatocellular carcinoma. NASH is the second leading indication for liver transplantation in the United States and is predicted to be the leading indication within the next decade. Despite the significant morbidity and mortality, the molecular mechanisms that lead to the development of NAFLD and progression to NASH are poorly understood, and there are no FDA-approved treatments. Endogenous growth hormone (GH) is reduced in obesity, and both clinical and preclinical data implicate GH in the etiopathology of NAFLD/NASH. GH is a critical stimulator of lipolysis, regulator of abdominal fat depots, an important immunomodulator and anti-inflammatory cytokine. However, the specific mechanisms of the effects of GH in NAFLD are poorly understood. The parent K23 award is a randomized, double-blind, placebo-controlled trial investigating the impact of GH administration on hepatic steatosis, inflammation and fibrosis in patients with overweight/obesity and NAFLD. The goal of this R03 proposal is to determine the molecular pathways that link the GH axis and NAFLD/NASH in humans using metabolomics, a powerful mass spectrometry-based technology that can identify unique metabolic signatures, pathogenic biomarkers, therapeutic drug targets, and predictors of treatment response in human disease. This R03 proposal utilizes targeted and unbiased metabolomic profiling in richly phenotyped cross-sectional and prospective cohorts from the parent K23 award to investigate the metabolic pathways engaged by GH, including de novo lipogenesis, lipid metabolism and bile acid metabolism. Aim 1 will identify GH-associated metabolites in our cross-sectional cohort and determine if these GH-associated metabolites are specifically associated with NAFLD. Aim 2 will leverage the prospective cohort randomized to GH vs placebo for six months in order to identify additional metabolites responsive to GH administration. We will then examine the association between these GH-responsive metabolites and changes in hepatic steatosis, inflammation and fibrosis with GH treatment. The goal of this R03 proposal is to build preliminary data for an R01 investigating the mechanisms of GH dysregulation in NAFLD and obesity and potential biomarkers of disease. In addition to providing preliminary data, the current proposal will serve as a training mechanism in metabolomics and will support Dr. Dichtel’s K-to-R transition towards a career as an independent, R01-funded researcher in the investigation of hormone systems in obesity, obesity-related complications and metabolic disease.