Fatty liver is the earliest and most common response of the liver to consumption of excessive alcohol. Steatosis can predispose the fatty liver to develop progressive liver damage. Chief among the many mechanisms involved in development of hepatic steatosis is dysregulation of insulin-mediated adipose tissue metabolism. Particularly, it is the enhanced adipose lipolysis-derived free fatty acids and their delivery to the liver that ultimately results in hepatic steatosis. The adipose-liver axis is modulated by hormones, particularly insulin and adiponectin. 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. Because many organs, including adipose tissue, express ghrelin receptor we hypothesized that ghrelin may directly affect energy metabolism in adipocytes. We have exciting new preliminary data which shows that treatment of premature 3T3-L1 adipocytes with ghrelin impairs adipocyte differentiation and inhibits lipid accumulation in the organ designed to store energy in the form of fat. We further observed that ghrelin treatment of differentiated adipocytes significantly inhibited secretion of adiponectin, a hepatoprotective hormone that reduces lipid synthesis and promotes lipid oxidation. These results were corroborated by our observations of a significant increase in serum adiponectin levels in ethanol-fed rats treated with a ghrelin receptor antagonist verses the un-treated ethanol-fed rats. Interestingly, in adipocytes, ghrelin also increases secretion of interleukin-6 (IL-6) and CCL2 (chemokine [C–C motif] ligand 2), cytokines which promote hepatic inflammation and progression of liver disease. To summarize, the alcohol-induced increase in serum ghrelin levels dysregulates adipose-liver interaction and promotes hepatic steatosis by increasing the free fatty acids released from adipose for hepatic uptake, and by altering adiponectin and cytokine secretion. Taken together, our data indicates that targeting the activity of ghrelin may be a powerful treatment strategy.

脂肪肝是肝脏对过量饮酒的最早和最常见的反应。脂肪变性可以使脂肪肝发展为进行性肝损伤。肝脏脂肪变性发展的许多机制中最主要的是胰岛素介导的脂肪组织代谢失调。特别是，增强的脂肪分解衍生的游离脂肪酸及其向肝脏的输送最终导致肝脏脂肪变性。脂肪肝轴受激素调节，尤其是胰岛素和脂联素。在我们最近的研究中，我们证明了酒精诱导的血清 ghrelin 水平升高会损害胰腺 β 细胞的胰岛素分泌。随之而来的循环胰岛素水平的降低促进了脂肪的脂肪分解和脂肪酸向肝脏的动员，最终导致肝脏脂肪变性。因为包括脂肪组织在内的许多器官都表达生长素释放肽受体，我们假设生长素释放肽可能直接影响脂肪细胞的能量代谢。我们有令人兴奋的新初步数据表明，用生长素释放肽治疗过早的 3T3-L1 脂肪细胞会损害脂肪细胞的分化并抑制旨在以脂肪形式储存能量的器官中的脂质积累。我们进一步观察到，生长素释放肽对分化的脂肪细胞的处理显着抑制了脂联素的分泌，脂联素是一种减少脂质合成并促进脂质氧化的保肝激素。我们观察到用生长素释放肽受体拮抗剂治疗的乙醇喂养的大鼠与未处理的乙醇喂养的大鼠相比，血清脂联素水平显着增加，这些结果得到了证实。有趣的是，在脂肪细胞中，ghrelin 还会增加白细胞介素 6 (IL-6) 和 CCL2（趋化因子 [C–C 基序] 配体 2）的分泌，这些细胞因子会促进肝脏炎症和肝脏疾病的进展。总而言之，酒精诱导的血清 ghrelin 水平升高会通过增加脂肪释放的用于肝脏摄取的游离脂肪酸以及改变脂联素和细胞因子的分泌来失调脂肪-肝脏相互作用并促进肝脏脂肪变性。总之，我们的数据表明，针对生长素释放肽的活性可能是一种有效的治疗策略。