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

 描述(申请人提供)：酒精性肝病(ALD)在美国和世界范围内都是一个主要的健康问题。脂肪肝(脂肪变性)是肝脏对过量酒精摄入的最早和最常见的反应，它使脂肪肝容易发展为酒精性脂肪性肝炎(ASH)、肝纤维化、肝硬变甚至肝细胞癌。在众多在酒精性肝脂肪变性发展中起作用的机制中，循环脂肪酸增加是核心机制。最近的证据表明，酒精诱导的脂肪组织动员导致循环中的脂肪酸增加，并增强了肝脏对随后脂肪积累的摄取。胰岛素会影响全身的脂肪代谢。胰岛素的两个重要代谢作用是：1)促进脂蛋白从肝脏输出储存在脂肪组织中；2)抑制脂肪细胞中的脂解作用。众所周知，慢性酒精暴露会破坏胰岛素依赖的信号转导，从而促进脂肪细胞的脂肪分解。在我们实验室最近的研究中，我们发现，不出所料，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的大鼠血浆Ghrelin水平增加。Ghrelin是一种主要由胃分泌的激素，它抑制胰腺β细胞的胰岛素分泌。另一种已知参与胰岛素分泌的蛋白质是Rab3D，它是一种依赖于钙离子的小Rab GTP酶。Rab3D的参与特别耐人寻味，因为我们最近报道，这种蛋白质在酒精喂养的大鼠的肝脏中急剧减少，并可能在酒精损伤的肝脏中改变蛋白质的运输中发挥作用。我们的初步数据显示，在酒精喂养的大鼠的胰岛中，Rab3D也减少了。在我们的初步数据的基础上，由于酒精处理的动物的胰岛胰岛素分泌显著减少，我们提出了以下假设：酒精诱导的血清Ghrelin水平的升高和胰腺Rab3D含量的减少都与胰腺β细胞的胰岛素分泌受损有关。因此，这些变化导致的循环中胰岛素水平的降低有助于 增加从脂肪组织到肝脏的脂肪酸动员，从而加剧肝脏脂肪变性。我们将利用各种最先进的技术来追求我们在这一应用中提出的新颖和创新的生物学概念，其中包括：第一，酒精摄入增加循环中的Ghrelin水平，导致胰腺β细胞胰岛素分泌受损；第二，酒精相关的Rab3D降低降低β细胞的胰岛素排泄；第三，增加Ghrelin和减少胰岛素共同调节肝脏和脂肪组织中的脂肪代谢，有利于肝脏脂肪变性；第四，Ghrelin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的Ghrelin和Rab3D在酒精暴露后调节胰腺-脂肪-肝轴中的作用提供新的见解。

 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.