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

7.项目总结/摘要 非酒精性脂肪肝（NALFD）是对公共卫生的日益严重的威胁：24%的成年人，超过一半的人， 肥胖或2型糖尿病（T2 D）患者患有NAFLD，这会增加肝衰竭、T2 D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。 虽然饮食和运动被证明可以改善NAFLD，但生活方式的改变对许多人来说很难维持。 患者目前，对于NAFLD还没有高效的药物治疗， 存在的治疗策略，以补充生活方式的改变。该提案研究了一种新的战略， 使用生长激素释放激素（GHRH）减少肝脏脂肪和炎症， 内源性GH分泌平均而言，肥胖者的生长激素水平显著降低， 分泌，我们假设有助于NAFLD的病理生理学，通过促进促- 炎症环境和改变肝脏脂质代谢，增加肝脏新生脂肪生成。我们 初步数据表明，GHRH降低了HIV感染者的肝脏脂肪， 个体，减少全身炎症，改善颈动脉内膜中层厚度， 亚临床动脉粥样硬化这些数据支持需要研究GHRH对肝脏脂肪和组织学的影响 在患有NAFLD的肥胖个体中。目前的研究是由合作的共同主要研究者提出的， 博士科里是一位肝病学家，在NAFLD方面具有重要的调查和临床研究经验。 斯坦利是一位内分泌学家，在激素动力学、脂质代谢和 使用GHRH。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名肥胖成人，肝活检证实NAFLD或磁共振成像证实肝脂肪分数≥5% 共振波谱（MRS）。在随机化阶段之后将进行6个月的开放标签阶段，以 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将显著降低肝脏脂肪，如通过MRS（主要 终点）和改善肝脏组织学，如通过NAFLD活动评分的降低及其个体 件.目的2：GHRH通过减少肝脏新生脂肪生成， 增加脂肪分解基因的表达，并且还将减少脂肪生成、促脂肪分解和促脂肪分解基因的肝表达。 炎症和纤维化基因。目标3：最后，鉴于心血管疾病是导致 初步数据强烈提示GHRH可降低NAFLD患者的亚临床死亡率， 动脉粥样硬化，我们假设GHRH将减少冠状动脉钙化评分和总斑块 并将改善血脂和心血管疾病的循环标志物。如果这些假设 正确的，拟议的研究将代表治疗发展的重大进展， NAFLD在肥胖中的作用

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.