Ghrelin regulates adipose tissue metabolism: Role in hepatic steatosis.

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 recent studies, we demonstrated that an alcohol-induced increase in serum ghrelin levels impairs insulin secretion from pancreatic β-cells. The consequent reduction in circulating insulin levels promotes adipose lipolysis and mobilization of fatty acids to the liver to ultimately contribute to hepatic steatosis. Because many tissues, 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 tissue 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 acid 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最早且最常见的反应。脂肪变性可使脂肪肝易于发生进行性肝损伤。在肝脂肪变性发生的众多机制中，主要的是胰岛素介导的脂肪组织代谢失调。特别是，脂肪分解增强所产生的游离脂肪酸及其向肝脏的输送最终导致肝脂肪变性。脂肪 - 肝脏轴受激素调节，尤其是胰岛素和脂联素。在近期研究中，我们证实酒精诱导的血清胃饥饿素水平升高会损害胰腺β细胞的胰岛素分泌。循环胰岛素水平随之降低促进脂肪分解以及脂肪酸向肝脏的动员，最终导致肝脂肪变性。由于包括脂肪组织在内的许多组织都表达胃饥饿素受体，我们假设胃饥饿素可能直接影响脂肪细胞的能量代谢。我们有令人兴奋的新的初步数据表明，用胃饥饿素处理未成熟的3T3 - L1脂肪细胞会损害脂肪细胞分化，并抑制旨在以脂肪形式储存能量的组织中的脂质积累。我们还观察到，用胃饥饿素处理分化的脂肪细胞会显著抑制脂联素的分泌，脂联素是一种具有肝脏保护作用的激素，可减少脂质合成并促进脂质氧化。我们观察到用胃饥饿素受体拮抗剂处理的乙醇喂养大鼠与未处理的乙醇喂养大鼠相比，血清脂联素水平显著升高，这进一步证实了上述结果。有趣的是，在脂肪细胞中，胃饥饿素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。总之，酒精诱导的血清胃饥饿素水平升高通过增加脂肪释放供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，从而失调脂肪 - 肝脏相互作用并促进肝脂肪变性。综上所述，我们的数据表明，针对胃饥饿素的活性可能是一种有效的治疗策略。