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: 10211947
• 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/10211947
• 关键词: Adipocytes; Adipose tissue; Affect; Agonist; Alcohol consumption; 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; Lead; 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; 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; antimicrobial peptide; base; carbohydrate metabolism; chronic alcohol ingestion; ghrelin; ghrelin receptor; glucagon-like peptide 1; 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.

摘要： 脂肪肝（脂肪变性），其特征在于肝细胞中脂质的积聚，是最早的病理性肝损害之一。 酒精相关性脂肪肝（AFLD）进展的变化。病理生理机制 在AFLD的发展过程中涉及的是复杂的和多因素的，包括肠道、胰腺和脂肪组织 据报道影响肝脏病理学的功能障碍。越来越多的证据表明 这些器官之间的联系是由肽激素调节的。与这一提议特别相关的是， 有兴趣了解肠道激素在器官相互作用和AFLD发展中的作用。 在所有胃肠激素中，胃源性胃饥饿素是其中一种 在人类和实验动物模型中，慢性酒精暴露会显著增加。在我们最近 研究表明，酒精诱导的血清ghrelin水平升高会损害胰岛素分泌， 胰腺β细胞。循环胰岛素水平的随之降低促进脂肪脂解， 脂肪酸向肝脏的移动最终导致肝脂肪变性。与此同时，慢性酒精 对大鼠的治疗增加了肠激素、胰高血糖素样肽-1（GLP-1）的血清水平，同时降低了 肝脏表达的抗菌肽-2（LEAP-2）和脂联素水平。有趣的是，这些病理 在乙醇喂养的生长激素释放肽受体敲除（GHS-R KO）大鼠中， 脂肪变性的发展。总的来说，这些结果表明酒精诱导的生长激素释放肽的基本作用， 增加影响多个器官，如肠道和脂肪，以调节GLP-1、胰岛素、脂联素和 LEAP-2活动/水平，最终导致AFLD的发展。 为了研究这些影响，我们提出以下假设：酒精诱导的血清ghrelin水平升高 直接（i）抑制肝细胞中GLP-1酶介导的能量代谢和（ii）调节 脂肪代谢，增加脂肪分解和减少脂联素分泌，这两个 导致肝脂肪变性。此外，生长激素释放肽还通过降低 LEAP-2，最近发现的内源性生长激素释放肽拮抗剂肽，减少生长激素释放肽受体 （GHS-R）介导的信号转导。 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 该假说有三个具体目的：1）表征ghrelin在调节肠源性GLP-1中的作用 AFLD发生发展过程中肠介导的肠-肝串扰; 2）表征AFLD发生发展过程中肠-肝串扰的特异性贡献。 生长激素释放肽在ALFD发展中调节脂肪-肝轴的作用;和3）检查酒精- 诱导的ghrelin增加LEAP-2表达，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了解生长激素释放肽的作用， 调节肠、脂肪和肝轴以促进酒精性脂肪变性的发展。