FGF21 and adipose lipolysis in alcoholic fatty liver

描述(申请人提供)：酒精性脂肪肝被认为是酒精性肝病(ALD)从肝脏脂肪变性发展到肝炎、纤维化、肝硬化甚至肝细胞癌的最早的病理改变。肝组织游离钙的反向转运 由酒精摄入引起的脂肪高脂分解所产生的脂肪酸(FFA)在脂肪肝的形成中起关键作用。然而，酒精调节脂肪组织脂肪分解的机制尚不清楚。近年来，成纤维细胞生长因子21(FGF21)已经成为一种肝脏调节因子，它作用于多个靶点，包括肝脏本身以自分泌的方式，重要的是作用于白色脂肪组织来调节脂质平衡。我们发现，在酒精性脂肪变性动物模型中，FGF21在酒精诱导的脂肪分解和肝脏脂肪蓄积中起关键作用，在ALD患者和实验动物模型中循环中FGF21水平显著升高。然而，FGF21如何调节酒精暴露期间的脂肪组织脂肪分解尚不清楚。本项目的目的是研究FGF21在酒精暴露下脂肪组织脂解反应中的作用，以加深我们对该激素在酒精性肝病中调节和作用的分子机制的理解，并评估其在酒精性脂肪肝形成中的治疗潜力。为实现这一目标，我们将落实以下具体目标。在目标1中，我们将利用FGF21基因敲除和转基因过表达的小鼠模型，确定FGF21在酒精暴露中是否在脂肪组织脂解中起刺激作用，以及与激素敏感脂肪酶和Perilipin途径相关的潜在机制。在第二个目标中，我们将通过脂肪选择性Klotho基因敲除小鼠来验证我们的假设，即脂肪组织特异性破坏FGF21减少FFA的释放和肝脏的摄取，并减轻酒精诱导的脂肪肝的形成。

DESCRIPTION (provided by applicant): Alcoholic fatty liver is considered as the earliest pathological alteration of progression in alcoholic liver disease (ALD) from hepatic steatosis to hepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma. Hepatic reverse transport of free fatty acids (FFAs) derived from adipose hyperlipolysis resulting from alcohol ingestion plays a critical role in fatty liver formation. However, the mechanisms by which alcohol regulates adipose tissue lipolysis are unclear. Recently, fibroblast growth factor 21 (FGF21) has emerged as a hepatic regulatory factor that acts on multiple targets, including the liver itself in an autocrine fashion, and importantly on white adipose tissue to regulate lipid homeostasis. We have found that FGF21 plays a critical role in alcohol-induced adipose lipolysis and in hepatic fat accumulation in animal models of ALD, and circulating FGF21 levels are significantly increased in patients with ALD and in experimental animal models. However, how FGF21 regulates adipose tissue lipolysis during alcohol exposure is not known. The aims of this project are to investigate the role of FGF21 in adipose tissue lipolysis in response to alcohol exposure to improve our understanding of the molecular mechanisms in the regulation and action of this hormone in ALD, and to assess the therapeutic potential in alcohol-induced fatty liver formation. To achieve this goal, we will carry out the following specific aims. In aim 1 we will determine whether FGF21 plays a stimulatory role in adipose tissue lipolysis and the underlying mechanisms associated with hormone sensitive lipase and perilipin pathway during alcohol exposure using FGF21 knockout and transgenic overexpression mouse models. In the second aim, we will test our hypothesis that adipose tissue specific disruption of FGF21 decreases FFA release and hepatic uptake and attenuates alcohol-induced fatty liver formation using adipose selective ¿-klotho knockout mice.