Growth Hormone Releasing Hormone Analog to Improve Nonalcoholic Fatty Liver Disease and Associated Cardiovascular Risk

7.项目摘要/摘要 非酒精性脂肪性肝病(NALFD)对公共健康的威胁越来越大：24%的成年人，超过一半的人 肥胖或2型糖尿病(T2D)的人患有NAFLD，这会增加患肝功能衰竭的风险， 和心血管疾病。预计到2020年，NAFLD将成为肝移植的主要适应症。 尽管饮食和锻炼被证明可以改善非酒精性脂肪肝，但生活方式的改变对许多人来说是难以维持的 病人。目前，非酒精性脂肪性肝病尚无高效的药物治疗方法，迫切需要 存在治疗策略来补充生活方式的改变。这项提案调查了一种新的战略，以 使用生长激素释放激素(GHRH)降低肝脏脂肪和炎症，它可以增加 内源性生长激素分泌。平均而言，肥胖患者的生长激素水平显著降低。 分泌，我们假设它有助于NAFLD的病理生理作用，促进一个促进- 炎症环境和改变肝脂代谢，增加肝脏新生脂肪生成。我们的 初步数据显示，GHRH降低了HIV感染者的肝脏脂肪，而在肥胖者中 减少全身炎症，改善颈动脉内膜-中层厚度，这是 亚临床动脉粥样硬化。这些数据支持有必要研究GHRH对肝脏脂肪和组织学的影响 患有非酒精性脂肪肝的肥胖者。目前的研究是由合作的联合首席调查员提出的， 科里博士是一位肝病学家，在NAFLD方面拥有丰富的研究和临床研究经验。 斯坦利是一位内分泌学家，在激素动力学、脂质代谢和 使用促性腺激素释放激素。该提案将在一项为期12个月的随机对照试验中调查GHRH的疗效 76名肥胖成年人，经肝活检确诊为非酒精性脂肪肝，或经磁学检查确诊为≥5%肝脂肪分数的成年人 共振光谱学(MRS)。在随机阶段之后将进行为期6个月的开放标签阶段，以便 为所有参与者提供接受积极治疗的机会。研究假设如下： 目的1：与安慰剂相比，GHRH将显著降低MRS(初级)测量的肝脏脂肪 终点)，并改善肝脏组织学，通过NAFLD活动评分及其个体的减少来评估 组件。目的2：促性腺激素释放激素通过减少肝脏新生脂肪生成而改变肝脏脂代谢。 增加脂解基因的表达，也会降低肝脏的生脂、促脂基因的表达。 炎症性和致纤维化基因。目标3：最后，鉴于心血管疾病是 NAFLD死亡，初步数据有力地表明GHRH有助于减少亚临床 我们假设GHRH将降低冠状动脉钙化积分和总斑块 负担，并将改善血脂和心血管疾病的循环标志物。如果这些假设是 正确，拟议的研究将代表着在开发治疗方法方面的重大进展 肥胖中的非酒精性脂肪肝。

7. Project Summary/Abstract Nonalcoholic fatty liver disease (NALFD) is a growing threat to public health: 24% of all adults, and over half of those with obesity or Type 2 diabetes (T2D), have NAFLD, which confers increased risk for liver failure, T2D, and cardiovascular disease. NAFLD is predicted to be the leading indication for liver transplantation by 2020. Although diet and exercise are proven to improve NAFLD, lifestyle changes are difficult to maintain for many patients. Currently there are no highly effective pharmacologic treatments for NAFLD, and significant need exists for therapeutic strategies to complement lifestyle changes. This proposal investigates a novel strategy to reduce liver fat and inflammation using growth hormone releasing hormone (GHRH), which augments endogenous GH secretion. On average, individuals with obesity have significant reductions in growth hormone secretion, which we hypothesize to contribute to the pathophysiology of NAFLD by promoting a pro- inflammatory milieu and altering hepatic lipid metabolism, increasing hepatic de novo lipogenesis. Our preliminary data demonstrate that GHRH decreases liver fat in HIV-infected individuals and, in obese individuals, reduces systemic inflammation and improves carotid intima-media thickness, a marker of subclinical atherosclerosis. These data support the need to study the effects of GHRH on liver fat and histology in obese individuals with NAFLD. The current research is proposed by collaborating Co-Principal Investigators, Dr. Corey, a hepatologist with significant investigative and clinical research experience in NAFLD, and Dr. Stanley, an endocrinologist with significant research experience in hormone dynamics, lipid metabolism, and use of GHRH. The proposal will investigate the efficacy of GHRH in a 12-month randomized controlled trial in 76 obese adults who have established NAFLD on liver biopsy or ≥5% hepatic fat fraction on magnetic resonance spectroscopy (MRS). A 6-month open-label phase will follow the randomized phase in order to provide all participants with the opportunity to receive active treatment. The study hypotheses are as follows: Aim 1: Compared to placebo, GHRH will significantly decrease hepatic fat as measured by MRS (primary endpoint) and improve liver histology as assessed by reduction in NAFLD activity score and its individual components. Aim 2: GHRH will alter hepatic lipid metabolism by decreasing hepatic de novo lipogenesis and increasing expression of lipolytic genes, and will also reduce the hepatic expression of lipogenic, pro- inflammatory and fibrogenic genes. Aim 3: Finally, given that cardiovascular disease is the leading cause of death in NAFLD, and that preliminary data strongly suggest a benefit of GHRH to reduce subclinical atherosclerosis, we hypothesize that GHRH will decrease coronary artery calcium scores and overall plaque burden and will improve lipids and circulating markers of cardiovascular disease. If these hypotheses are correct, the proposed studies will represent significant progress toward the development of therapies for NAFLD in obesity.