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

项目总结 非酒精性脂肪性肝病(NAFLD)是一种与体重相关的严重并发症，80%的患者出现这种并发症 美国肥胖症患者的比例。非酒精性脂肪性肝炎(NASH)，进行性形式的 非酒精性脂肪肝以炎症、细胞死亡和纤维化为特征，可导致肝硬变、失代偿 肝脏疾病和肝细胞癌。NASH是年肝移植的第二大适应症 美国，并预计将在未来十年内成为领先的迹象。 尽管发病率和死亡率很高，但导致这种疾病发生的分子机制 对NAFLD的发生和进展到NASH的了解很少，也没有FDA批准的治疗方法。 内源性生长激素(GH)在肥胖患者中减少，临床和临床前数据都表明GH与肥胖有关 NAFLD/NASH的发病机制。生长激素是脂解的重要刺激因子，是腹部脂肪库的调节者，也是 重要的免疫调节剂和抗炎细胞因子。然而，其作用的具体机制 对NAFLD中的GH知之甚少。 家长K23奖是一项随机、双盲、安慰剂对照试验，调查 GH对超重/肥胖和NAFLD患者肝脏脂肪变性、炎症和纤维化的影响 R03提案的目标是确定连接GH轴和NAFLD/NASH的分子路径 在人类中使用代谢组学，这是一种强大的基于质谱学的技术，可以识别独特的 代谢特征、致病生物标记物、治疗药物靶点和治疗反应的预测因素 人类疾病。 这份R03提案利用靶向和无偏见的代谢组图谱在丰富的表型中 来自父母K23奖的横断面和前瞻性队列研究代谢 生长激素参与的途径包括新生脂肪生成、脂代谢和胆汁酸代谢。 目标1将在我们的横断面队列中识别与生长激素相关的代谢物，并确定这些与生长激素相关的 代谢产物与非酒精性脂肪性肝病有特殊的关系。目标2将利用随机分组的预期队列 GH与安慰剂比较六个月，以确定对GH注射有反应的其他代谢物。我们会 然后检查这些生长激素反应代谢物和肝脏脂肪变性变化之间的关系， 生长激素治疗后的炎症和纤维化。 R03提案的目标是为研究生长激素机制的R01建立初步数据 非酒精性脂肪性肝病与肥胖和潜在的疾病生物标记物的失调。除了提供初步的 数据，目前的提议将作为代谢组学的培训机制，并将支持Dr。 Dichtel从K到R的转变，成为一名独立的，由R01资助的 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.