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.

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