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

生长激素释放激素类似物可改善非酒精性脂肪肝及相关心血管风险

• 批准号: 9522472
• 负责人: Kathleen Elizabeth Corey
• 金额: $ 80.03万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9522472
• 关键词: Accounting; Address; Adipose tissue; Adult; Adverse effects; Affect; Alteplase; American; Antigens; Atherosclerosis; Biopsy; C-reactive protein; CCL2 gene; COL1A1 gene; Cardiovascular Diseases; Cause of Death; Cessation of life; Cirrhosis; Clinical Research; Complement; Data; Endocrinologist; Endocrinology; FDA approved; Fatty acid glycerol esters; Fibrosis; Frequencies; Functional disorder; General Hospitals; General Population; Genes; HIV; Heart Diseases; Hepatic; Hepatocyte; Hepatology; High Density Lipoproteins; Histologic; Histology; Hormone secretion; Hormones; Individual; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-18; Interleukin-6; Interstitial Collagenase; Investigation; Lead; Life Style; Lipids; Liver; Liver Failure; Liver diseases; Lobular; Magnetic Resonance Spectroscopy; Massachusetts; Measures; Mediator of activation protein; Metabolic; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Obesity; PPAR alpha; Participant; Pathogenesis; Patients; Pharmacological Treatment; Pharmacology; Phase; Phenotype; Physiological; Physiology; Pioglitazone; Placebos; Plasminogen Activator Inhibitor 1; Population; Principal Investigator; Prospective cohort; Public Health; RANTES; Randomized; Randomized Controlled Trials; Research; Research Methodology; Risk; Role; Somatotropin; Somatotropin-Releasing Hormone; TIMP1 gene; TNF gene; Testing; Therapeutic; Visceral; Vitamin E; active method; adiponectin; adult obesity; animal data; cardiometabolic risk; cardiometabolism; cardiovascular disorder risk; cardiovascular risk factor; carotid intima-media thickness; circulating biomarkers; coronary calcium scoring; design; diabetes risk; diet and exercise; experience; hormone analog; improved; indexing; inflammatory milieu; lipid biosynthesis; lipid metabolism; liver biopsy; liver imaging; liver inflammation; liver injury; liver transplantation; mortality; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel strategies; open label; patient subsets; primary endpoint; recruit; stable isotope; therapy development; treatment strategy

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.

7. 项目总结/摘要 非酒精性脂肪肝 (NALFD) 对公共健康的威胁日益严重：占所有成年人的 24%，超过一半的人患有非酒精性脂肪肝 (NALFD)。 肥胖或 2 型糖尿病 (T2D) 患者患有 NAFLD，这会增加肝衰竭、T2D 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。 尽管饮食和锻炼已被证明可以改善 NAFLD，但对许多人来说，生活方式的改变很难维持 患者。目前尚无针对 NAFLD 的高效药物治疗方法，迫切需要 存在补充生活方式改变的治疗策略。该提案研究了一种新颖的策略 使用生长激素释放激素 (GHRH) 减少肝脏脂肪和炎症，该激素可增强 内源性 GH 分泌。平均而言，肥胖者的生长激素显着减少 分泌，我们假设它通过促进促 NAFLD 的病理生理学 炎症环境并改变肝脏脂质代谢，增加肝脏从头脂肪生成。我们的 初步数据表明，GHRH 可降低 HIV 感染者和肥胖者的肝脏脂肪 个人，减少全身炎症并改善颈动脉内膜中层厚度，这是颈动脉的标志 亚临床动脉粥样硬化。这些数据支持研究 GHRH 对肝脏脂肪和组织学影响的必要性 患有 NAFLD 的肥胖个体。目前的研究是由合作联合首席研究员提出的， Corey 博士是一位肝病学家，在 NAFLD 方面拥有丰富的调查和临床研究经验。 Stanley 是一位内分泌学家，在激素动力学、脂质代谢和内分泌方面具有丰富的研究经验 GHRH 的使用。该提案将在一项为期 12 个月的随机对照试验中调查 GHRH 的功效 76 名经肝活检确诊为 NAFLD 或经磁力检测肝脂肪分数≥5% 的肥胖成人 共振光谱（MRS）。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： 目标 1：与安慰剂相比，根据 MRS 测量，GHRH 将显着降低肝脂肪（主要 终点）并改善肝脏组织学（通过 NAFLD 活动评分及其个体的降低来评估） 成分。目标 2：GHRH 将通过减少肝脏从头脂肪生成来改变肝脏脂质代谢， 增加脂肪分解基因的表达，并且还会减少脂肪生成、促脂肪基因的肝脏表达 炎症和纤维化基因。目标 3：最后，考虑到心血管疾病是导致糖尿病的主要原因 NAFLD 死亡，初步数据强烈表明 GHRH 有助于减少亚临床症状 动脉粥样硬化，我们假设 GHRH 会降低冠状动脉钙分数和总体斑块 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 正确的是，拟议的研究将代表开发治疗方法的重大进展 NAFLD 与肥胖有关。