Department of Internal Medicine, University of Nebraska Medical Center , Omaha, Nebraska.
Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska.
Am J Physiol Gastrointest Liver Physiol. 2019 Apr 1;316(4):G453-G461. doi: 10.1152/ajpgi.00334.2018. Epub 2019 Jan 31.
Fatty liver is the earliest response of the liver to excessive ethanol consumption. Central in the development of alcoholic steatosis is increased mobilization of nonesterified free fatty acids (NEFAs) to the liver from the adipose tissue. In this study, we hypothesized that ethanol-induced increase in ghrelin by impairing insulin secretion, could be responsible for the altered lipid metabolism observed in adipose and liver tissue. Male Wistar rats were fed for 5-8 wk with control or ethanol Lieber-DeCarli diet, followed by biochemical analyses in serum and liver tissues. In addition, in vitro studies were conducted on pancreatic islets isolated from experimental rats. We found that ethanol increased serum ghrelin and decreased serum insulin levels in both fed and fasting conditions. These results were corroborated by our observations of a significant accumulation of insulin in pancreatic islets of ethanol-fed rats, indicating that its secretion was impaired. Furthermore, ethanol-induced reduction in circulating insulin was associated with lower adipose weight and increased NEFA levels observed in these rats. Additionally, we found that increased concentration of serum ghrelin was due to increased synthesis and maturation in the stomach of the ethanol-fed rats. We also report that in addition to its effect on the pancreas, ghrelin can also directly act on hepatocytes via the ghrelin receptors and promote fat accumulation. In conclusion, alcohol-induced elevation of circulating ghrelin levels impairs insulin secretion. Consequently, reduced circulating insulin levels likely contribute to increased free fatty acid mobilization from adipose tissue to liver, thereby contributing to hepatic steatosis. NEW & NOTEWORTHY Our studies are the first to report that ethanol-induced increases in ghrelin contribute to impaired insulin secretion, which results in the altered lipid metabolism observed in adipose and liver tissue in the setting of alcoholic fatty liver disease.
脂肪肝是肝脏对过量乙醇摄入的最早反应。在酒精性脂肪变性的发展中，关键是从脂肪组织向肝脏增加非酯化游离脂肪酸 (NEFA) 的动员。在这项研究中，我们假设乙醇通过损害胰岛素分泌而增加胃饥饿素的产生，可能是导致观察到脂肪组织和肝脏组织中脂质代谢改变的原因。雄性 Wistar 大鼠用对照或乙醇 Lieber-DeCarli 饮食喂养 5-8 周，然后进行血清和肝组织的生化分析。此外，还对来自实验大鼠的胰腺胰岛进行了体外研究。我们发现，乙醇在进食和禁食条件下均增加血清胃饥饿素并降低血清胰岛素水平。这些结果得到了我们的观察结果的证实，即在乙醇喂养的大鼠中，胰岛中胰岛素的大量积累表明其分泌受损。此外，乙醇诱导的循环胰岛素减少与这些大鼠中观察到的脂肪重量降低和游离脂肪酸水平升高有关。此外，我们发现血清胃饥饿素浓度的增加是由于乙醇喂养大鼠胃中合成和成熟增加所致。我们还报告说，除了对胰腺的作用外，胃饥饿素还可以通过胃饥饿素受体直接作用于肝细胞并促进脂肪堆积。总之，酒精引起的循环胃饥饿素水平升高会损害胰岛素分泌。因此，循环胰岛素水平降低可能导致从脂肪组织向肝脏动员游离脂肪酸增加，从而导致脂肪肝。新的和值得注意的是，我们的研究首次报道，乙醇诱导的胃饥饿素增加导致胰岛素分泌受损，这导致酒精性脂肪肝疾病中观察到的脂肪组织和肝脏组织中脂质代谢改变。
