FGF21 and adipose lipolysis in alcoholic fatty liver

FGF21 与酒精性脂肪肝中的脂肪分解

• 批准号: 8702281
• 负责人: WENKE FENG
• 金额: $ 21.56万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702281
• 关键词: Adipose tissue; Alcohol consumption; Alcoholic Fatty Liver; Alcoholic Liver Diseases; Alcohols; Animal Model; Attenuated; Body fat; Calories; Capsid Proteins; Catecholamines; Chronic; Cirrhosis; Cyclic AMP; Data; Deuterium; Development; Endocrine; Epidemiologic Studies; Ethanol; Experimental Animal Model; Exposure to; Fatty Liver; Fatty acid glycerol esters; Fibroblast Growth Factor; Fibrosis; Goals; Hepatic; Hepatitis; Hepatocyte; Homeostasis; Hormones; Hyperlipidemia; Incubated; Insulin; Knock-out; Knockout Mice; Label; Lipids; Lipolysis; Liver; Liver diseases; Mediating; Mediator of activation protein; Metabolic; Molecular; Nicotinic Acids; Nonesterified Fatty Acids; Pathway interactions; Patients; Phosphorylation; Plasma; Play; Primary carcinoma of the liver cells; Recombinant Fibroblast Growth Factor; Regulation; Reporting; Resistance; Rodent; Role; Serum; Signal Transduction; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Triglycerides; Wild Type Mouse; alcohol exposure; alcohol response; autocrine; base; deprivation; fatty acid transport; feeding; fibroblast growth factor 21; improved; lipid biosynthesis; lipid metabolism; meetings; member; mouse model; overexpression; oxidation; perilipin; problem drinker; public health relevance; receptor; response; sterol esterase; uptake

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.

描述（由申请人提供）：酒精性脂肪肝被认为是酒精性肝病（ALD）从肝脂肪变性进展为肝炎、纤维化、肝硬化甚至肝细胞癌的最早病理改变。肝游离反转运 脂肪酸（FFA）来源于酒精摄入引起的脂肪分解过度，在脂肪肝形成中起关键作用。然而，酒精调节脂肪组织脂解的机制尚不清楚。最近，成纤维细胞生长因子21（FGF 21）已经作为肝脏调节因子出现，其作用于多个靶点，包括以自分泌方式作用于肝脏本身，并且重要地作用于白色脂肪组织以调节脂质稳态。我们已经发现，FGF 21在酒精诱导的脂肪分解和ALD动物模型中的肝脂肪积累中起关键作用，并且在ALD患者和实验动物模型中循环FGF 21水平显著增加。然而，FGF21在酒精暴露期间如何调节脂肪组织脂解尚不清楚。该项目的目的是研究FGF21在酒精暴露引起的脂肪组织脂解中的作用，以提高我们对这种激素在ALD中的调节和作用的分子机制的理解，并评估酒精诱导的脂肪肝形成的治疗潜力。为实现这一目标，我们将实现以下具体目标。在目标1中，我们将使用FGF21敲除和转基因过表达小鼠模型确定FGF21是否在脂肪组织脂解中起刺激作用以及在酒精暴露期间与激素敏感性脂肪酶和周脂蛋白途径相关的潜在机制。在第二个目标中，我们将测试我们的假设，即脂肪组织特异性破坏FGF21减少FFA释放和肝脏摄取，并使用脂肪选择性klotho基因敲除小鼠减弱酒精诱导的脂肪肝形成。