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

项目摘要 非酒精性脂肪性肝病（NAFLD）是一种严重的体重相关并发症，80%的患者存在 肥胖症患者的比例。非酒精性脂肪性肝炎（NASH）， NAFLD的特征是炎症、细胞死亡和纤维化，其可导致肝硬化、失代偿 肝病和肝细胞癌。NASH是肝移植的第二大适应症， 美国，预计将成为未来十年的主要指标。 尽管发病率和死亡率很高，但导致发展的分子机制 对NAFLD和NASH进展的了解很少，并且没有FDA批准的治疗方法。 内源性生长激素（GH）在肥胖症中减少，临床和临床前数据都表明GH与肥胖症有关。 NAFLD/NASH的发病机制。生长激素是脂肪分解的关键刺激物，腹部脂肪库的调节剂， 重要免疫调节剂和抗炎细胞因子。然而，影响的具体机制， NAFLD中的GH知之甚少。 K23大奖是一项随机、双盲、安慰剂对照试验，旨在研究 GH给药对超重/肥胖和NAFLD患者的肝脂肪变性、炎症和纤维化的影响 本R 03提案的目标是确定连接GH轴和NAFLD/NASH的分子途径 在人类中使用代谢组学，一种强大的基于质谱的技术，可以识别独特的 代谢特征、致病生物标志物、治疗药物靶点和治疗反应的预测因子。 人类疾病 该R 03提案在丰富的表型中利用靶向和无偏倚的代谢组学分析， 来自母公司K23奖的横断面和前瞻性队列，以研究代谢 GH参与的途径，包括从头脂肪生成、脂质代谢和胆汁酸代谢。 目的1将在我们的横断面队列中识别GH相关代谢物，并确定这些GH相关代谢物是否与GH相关。 代谢物与NAFLD特异性相关。目标2将利用随机分配的前瞻性队列， GH与安慰剂持续6个月，以确定对GH给药有反应的其他代谢产物。我们将 然后检查这些GH反应性代谢物与肝脂肪变性变化之间的关联， 炎症和纤维化。 该R 03提案的目标是为研究GH机制的R 01建立初步数据 在NAFLD和肥胖症中的调节异常以及疾病的潜在生物标志物。除了提供初步的 数据，目前的建议将作为代谢组学的培训机制，并将支持博士。 Dichtel的K-to-R过渡到职业生涯作为一个独立的，R 01资助的研究人员在 肥胖、肥胖相关并发症和代谢性疾病中激素系统的研究。

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.