FGF21 and adipose lipolysis in alcoholic fatty liver

FGF21 与酒精性脂肪肝中的脂肪分解

基本信息

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
项目类别：
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

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

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项目摘要

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（由适用提供）：酒精性脂肪肝被认为是酒精性肝病（ALD）从肝炎到肝炎，纤维化，肝硬化甚至肝细胞癌的最早病理改变。肝反向自由运输源自脂肪过度分解的脂肪酸（FFA）在饮酒中引起的脂肪酸（FFA）在脂肪肝形成中起着至关重要的作用。但是，尚不清楚酒精调节脂肪组织脂解的机制。最近，成纤维细胞生长因子21（FGF21）已成为一种肝调节因子，其作用于多个靶标，包括肝脏本身以自分泌方式，并且重要的是对白色脂肪组织进行调节以调节脂质稳态。我们发现，FGF21在ALD的动物模型中在酒精诱导的脂肪脂解和肝脂肪积累中起着至关重要的作用，并且在ALD和实验动物模型中，循环FGF21水平显着增加。但是，FGF21在酒精暴露期间如何调节脂肪组织脂解。该项目的目的是研究FGF21在脂肪组织脂解中对酒精暴露的作用，以提高我们对该骑马酮在ALD中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中的治疗潜力。为了实现这一目标，我们将执行以下特定目标。在AIM 1中，我们将确定FGF21在使用FGF21敲除和转基因过表达小鼠模型的酒精暴露期间在脂肪组织脂解中起刺激作用，以及与雌酮敏感脂肪酶和perillipin途径相关的基本机制。在第二个目标中，我们将检验我们的假设，即FGF21的脂肪组织特异性破坏会降低FFA释放和肝摄取，并使用脂肪选择性粘贴型 - klotho敲除小鼠，可减少酒精诱导的脂肪肝脏形成。