Pancreas-Adipose-Liver Axis: Role of Ghrelin and Insulin in Alcoholic Fatty Liver

胰腺-脂肪-肝轴：生长素释放肽和胰岛素在酒精性脂肪肝中的作用

• 批准号: 9268735
• 负责人: Karuna Rasineni
• 金额: $ 12.06万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-05 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9268735
• 关键词: Adipocytes; Adipose tissue; Alcohol consumption; Alcoholic Fatty Liver; Alcoholic Liver Diseases; Alcohols; Animals; Attenuated; Beta Cell; Biological; Cell Line; Cells; Chronic; Cirrhosis; Data; Data Reporting; Deposition; Development; Diet; Ethanol; Exocytosis; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Goals; Health; Hepatic; Hepatocyte; Hormones; Impairment; In Vitro; Injury; Insulin; Insulin Resistance; Islets of Langerhans; Knockout Mice; Laboratories; Lipolysis; Lipoproteins; Liver; Liver Fibrosis; Liver diseases; Metabolic; Modeling; Mus; Organ; Pancreas; Pathway interactions; Plasma; Plasmids; Play; Predisposition; Primary carcinoma of the liver cells; Proteins; Rattus; Reporting; Resistance; Role; Serum; Signal Transduction; Small Interfering RNA; Steatohepatitis; Stomach; Structure of beta Cell of islet; Technology; Testing; Transgenes; Triglycerides; Work; alcohol effect; alcohol exposure; feeding; ghrelin; ghrelin receptor; improved; in vivo; injured; insight; insulin secretion; lipid metabolism; mRNA Expression; novel; overexpression; problem drinker; protein transport; public health relevance; rab GTP-Binding Proteins; response; uptake

 DESCRIPTION (provided by applicant): Alcohol-induced liver disease (ALD) is a major health problem both in the US and worldwide. Fatty liver (steatosis) is the earliest and most common response of the liver to excessive ethanol consumption that predisposes the fatty liver to develop alcoholic steatohepatitis (ASH), hepatic fibrosis, cirrhosis and even hepatocellular carcinoma. Central among the many mechanisms proposed to play a role in the development of alcoholic hepatic steatosis is increased circulating fatty acids. Recent evidence suggests that alcohol-induced mobilization from adipose tissue is responsible for the increased circulating fatty acids and their enhanced hepatic uptake for subsequent fat accumulation. Insulin influences lipid metabolism throughout the body. Two of the important metabolic actions of insulin are to 1) promote the export of lipoproteins from the liver for storage in adipose tissue and 2) inhibit lipolysis in adipocytes. It is known that chronic ethanol exposure in rats disrupts insulin-dependent signal transduction thereby promoting lipolysis in adipocytes. In recent studies from our laboratory we found that chronic alcohol feeding, as expected, decreased plasma insulin levels. In addition, surprisingly, we also found increased plasma ghrelin levels in chronic alcohol-fed rats. Ghrelin, a hormone mainly secreted from stomach, inhibits insulin secretion from pancreatic β-cells. Another protein known to be involved in insulin secretion is Rab3D, a small Ca2+-dependent Rab GTPase. Involvement of Rab3D is especially intriguing since we have recently reported that this protein is dramatically reduced in livers of ethanol-fed rats, and likely plays a role in altered protein trafficking in the alcohol-injured liver. Our preliminary data reported here shows that Rab3D is also decreased in pancreatic islets of ethanol-fed rats. On the basis of our preliminary data, and since insulin secretion has been shown to be significantly decreased in pancreatic islets of ethanol treated animals, we put forth the following hypothesis: Alcohol-induced increase in serum ghrelin levels and decrease in pancreatic Rab3D content both contribute to impaired insulin secretion from pancreatic β-cells. Consequently, the reduced circulating insulin levels resulting from these alterations contribute to increased fatty acid mobilization from adipose tissue to liver, thereby exacerbating hepatic steatosis. We will utilize a variety of state-of-the art technologies to pursue novel and innovativ biological concepts that we have put forth in this application that include: one, alcohol administration elevates circulating ghrelin levels, resulting in impaired insulin secretion by pancreatic β-cells; two, ethanol-associated lowering of Rab3D impairs insulin exocytosis in β-cells; three, increased ghrelin and reduced insulin work together to modulate fat metabolism in liver and adipose tissue favoring hepatic steatosis, and four, antagonists of ghrelin could help attenuate alcohol-induced organ injury. Successful completion of these studies will provide new insights on the roles of the important players, ghrelin and Rab3D, in modulating the pancreas-adipose-liver axis after alcohol exposure.

 描述（由申请人提供）：酒精性肝病（ALD）是美国和世界范围内的主要健康问题。脂肪肝（脂肪变性）是肝脏对过量乙醇消耗的最早和最常见的反应，其使脂肪肝易于发展成酒精性脂肪性肝炎（ASH）、肝纤维化、肝硬化甚至肝细胞癌。在酒精性肝脂肪变性的发展中发挥作用的许多机制中，中心是循环脂肪酸增加。最近的证据表明，酒精诱导的动员从脂肪组织是负责增加循环脂肪酸和增强肝脏摄取随后的脂肪积累。胰岛素影响全身的脂质代谢。胰岛素的两个重要代谢作用是1）促进脂蛋白从肝脏输出以储存在脂肪组织中和2）抑制脂肪细胞中的脂解。已知大鼠长期暴露于乙醇会破坏胰岛素依赖性信号转导，从而促进脂肪细胞的脂解。在我们实验室最近的研究中，我们发现，正如预期的那样，长期饮酒会降低血浆胰岛素水平。此外，令人惊讶的是，我们还发现慢性酒精喂养大鼠的血浆ghrelin水平增加。Ghrelin是一种主要由胃分泌的激素，它抑制胰岛β细胞分泌胰岛素。另一种已知参与胰岛素分泌的蛋白质是Rab 3D，一种小的Ca 2+依赖性Rab GT3。Rab 3D的参与特别有趣，因为我们最近报道，这种蛋白质在乙醇喂养的大鼠肝脏中显着减少，并且可能在酒精损伤的肝脏中改变蛋白质运输中发挥作用。我们的初步数据显示，Rab 3D在乙醇喂养的大鼠胰岛中也减少。基于我们的初步数据，并且由于乙醇处理的动物的胰岛中的胰岛素分泌已显示出显著降低，我们提出以下假设：酒精诱导的血清生长素释放肽水平的增加和胰腺Rab 3D含量的降低均有助于胰腺β细胞的胰岛素分泌受损。因此，由这些改变引起的循环胰岛素水平降低有助于 增加脂肪酸从脂肪组织向肝脏的移动，从而加重肝脂肪变性。我们将利用各种最先进的技术来追求我们在本申请中提出的新颖和创新的生物学概念，包括：一，酒精给药提高循环ghrelin水平，导致胰腺β细胞的胰岛素分泌受损;二，乙醇相关的Rab 3D降低损害β细胞中的胰岛素胞吐作用;第三，增加的生长素释放肽和减少的胰岛素共同调节肝脏和脂肪组织中的脂肪代谢，有利于肝脂肪变性;第四，生长素释放肽的拮抗剂可以帮助减轻酒精诱导的器官损伤。这些研究的成功完成将为重要参与者ghrelin和Rab 3D在酒精暴露后调节胰腺-脂肪-肝脏轴中的作用提供新的见解。