Role of alcohol-induced ghrelin in modulating organ crosstalk to promote the development of fatty liver disease

酒精诱导的胃饥饿素在调节器官串扰促进脂肪肝发展中的作用

• 批准号: 10625844
• 负责人: Karuna Rasineni
• 金额: $ 33.92万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625844
• 关键词: Adipocytes; Adipose tissue; Affect; Agonist; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Animal Model; Attenuated; Benign; Biological; Chronic; Cirrhosis; Complex; Development; Energy Metabolism; Ethanol; Experimental Animal Model; Fatty Acids; Fatty Liver; Fibrosis; Functional disorder; Gastrointestinal Hormones; Goals; Hepatic; Hepatitis; Hepatocyte; Hormones; Human; Impairment; In Vitro; Inflammation Mediators; Insulin; Knock-out; Lipids; Lipolysis; Liver; Liver diseases; Malignant Neoplasms; Mediating; Metabolic Diseases; Metabolism; Nonesterified Fatty Acids; Organ; Pancreas; Pathogenesis; Pathologic; Pathology; Peptides; Rattus; Receptor Mediated Signal Transduction; Reporting; Resistance; Role; Serum; Signal Transduction; Stomach; Structure of beta Cell of islet; Technology; Testing; Therapeutic Intervention; Therapeutic Uses; adipokines; adiponectin; alcohol abuse therapy; alcohol effect; alcohol exposure; antagonist; antimicrobial peptide; carbohydrate metabolism; chronic alcohol ingestion; fatty liver disease; ghrelin; ghrelin receptor; glucagon-like peptide 1; hepatoprotective; improved; innovation; insight; insulin secretion; insulin sensitivity; interest; lipid metabolism; oxidation; peptide hormone; prevent; problem drinker; targeted treatment; uptake

ABSTRACT: Fatty liver (steatosis), characterized by an accumulation of lipids in hepatocytes, is one of the earliest pathological changes in the progression of alcohol-associated fatty liver disease (AFLD). Pathophysiological mechanisms involved during development of AFLD are complex and multifactorial, including gut, pancreas and adipose tissue dysfunctions that reportedly affect liver pathology. Accumulating evidence has demonstrated that the crosstalk between these organs are regulated by peptide hormones. Especially relevant to this proposal is the growing interest in understanding the role of gut hormones in organ interactions and in the development of AFLD. Among all the gastrointestinal hormones, the stomach-derived ghrelin is the one of the hormones that significantly increases with chronic alcohol exposure in humans and experimental animal models. In our recent studies, we demonstrated that an alcohol-induced increase in serum ghrelin levels impairs insulin secretion from pancreatic β-cells. The consequent reduction in the circulating insulin levels promotes adipose lipolysis and mobilization of fatty acids to the liver to ultimately contribute to hepatic steatosis. Concomitantly, chronic alcohol treatment to rats increases serum levels of the gut hormone, glucagon-like peptide-1 (GLP-1) while decreasing liver-expressed antimicrobial peptide-2 (LEAP-2) and adiponectin levels. Interestingly, these pathological changes were not altered in ethanol-fed ghrelin receptor knockout (GHS-R KO) rats, which were also resistant to steatosis development. Collectively, these results indicate a fundamental role of an alcohol-induced ghrelin increase in affecting multiple organs, such as the gut and adipose to modulate GLP-1, insulin, adiponectin and LEAP-2 activity/levels, to ultimately lead to the development of AFLD. To study these effects, we present the following hypothesis: Alcohol-induced increase in serum ghrelin levels directly (i) inhibits GLP-1 hormone-mediated energy metabolism in hepatocytes and (ii) modulates adipose metabolism to increase adipose lipolysis and decrease adiponectin secretion, both of which contribute to hepatic steatosis. Furthermore, ghrelin also enhances its effects by lowering the levels of LEAP-2, recently discovered endogenous ghrelin antagonist peptide that reduces the ghrelin receptor (GHS-R) mediated signal transduction. We will utilize a variety of state-of-the art technologies and innovative biological concepts to explore our hypothesis in three specific aims: 1) Characterize the role of ghrelin in modulating the gut-derived GLP-1 hormone-mediated gut-liver crosstalk during the development of AFLD; 2) Characterize the specific contribution of ghrelin in modulating the adipose-liver axis in the development of ALFD; and 3) Examine the effect of alcohol- induced ghrelin increase on LEAP-2 expression and characterize its role in modulating hepatic steatosis. Successful completion of the proposed studies will aid mechanistic insights into understanding ghrelin’s role in modulating the gut, adipose and liver axis to promote the development of alcoholic steatosis.

抽象的： 脂肪肝（脂肪变性）的特征是肝细胞中脂质的积累，是最早的病理之一 酒精相关脂肪肝病（AFLD）的进展变化。病理生理机制 在AFLD开发过程中所涉及的复杂和多因素，包括肠道，胰腺和脂肪组织 据报道会影响肝脏病理学的功能障碍。积累的证据表明串扰 在这些器官之间受到意大利辣味激素的调节。与该提议特别相关的是增长 对了解肠激素在器官相互作用和AFLD发展中的作用的兴趣。 在所有胃肠道激素中，摊位衍生的生长素是一种激素之一 人类和实验动物模型中的慢性酒精暴露会显着增加。在我们的最新消息中 研究，我们表明，酒精诱导的血清生长素素水平的升高损害了胰岛素的分泌 胰腺β细胞。随之而来的循环胰岛素水平的降低会促进脂肪脂解和 将脂肪酸动员到肝脏最终导致肝脂肪变性。同时，慢性酒精 对大鼠的治疗增加肠马的血清水平，胰高血糖素样肽-1（GLP-1），同时降低 肝表达的抗菌胡椒2（LEAP-2）和脂联素水平。有趣的是，这些病理 乙醇喂养的生长素受体敲除（GHS-R KO）大鼠的变化没有改变，这也是抗性的 脂肪变性发育。总的来说，这些结果表明酒精诱导的生长素素的基本作用 增加影响多个器官的增加，例如肠道和脂肪调节GLP-1，胰岛素，脂联素和 LEAP-2活动/水平，最终导致AFLD的发展。 为了研究这些效果，我们提出以下假设：酒精诱导的血清生长素素水平的升高 直接（i）抑制肝细胞中的GLP-1马介导的能量代谢和（ii）调节 脂肪代谢增加脂肪脂解并减少脂联素的分泌 有助于肝脂肪变性。此外，生长素还通过降低水平来增强其影响 Leap-2，最近发现的内源性生长素蛋白拮抗剂胡椒，可降低生长素素受体 （GHS-R）介导的信号转移。 我们将利用各种最先进的技术和创新的生物学概念来探索我们的 三个特定目的的假设：1）表征生长素蛋白在调节肠道衍生的GLP-1中的作用 在AFLD的发展过程中，马龙介导的肠肝串扰； 2）表征特定的贡献 在调节Alfd的发育中调节脂肪肝轴时的生长素释放蛋白； 3）检查酒精的影响 LEAP-2表达诱导的生长素释放蛋白增加，并表征其在调节肝脂肪变性中的作用。 成功完成拟议的研究将有助于理解Ghrelin在 调节肠道，脂肪和肝轴以促进酒精脂肪变性的发展。