Adipose Tissue Lipolysis and Alcoholic Fatty Liver

脂肪组织脂解与酒精性脂肪肝

• 批准号: 8317733
• 负责人: ZHANXIANG ZHOU
• 金额: $ 28.21万
• 依托单位: UNIVERSITY OF NORTH CAROLINA GREENSBORO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8317733
• 关键词: Accounting; Adipocytes; Adipose tissue; Adrenergic Receptor; Affect; Alcohol consumption; Alcoholic Fatty Liver; Alcoholic Liver Diseases; Alcoholism; Alcohols; Attenuated; Body fat; CD36 Antigens; CD36 gene; Chronic; Clinical Research; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Deposition; Development; Dietary Zinc; Disease; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fatty-acid synthase; Fibrosis; Glucocorticoids; Hepatic; Hepatic Mass; Hepatitis; Hepatocyte; Homeostasis; Inflammation Mediators; Lead; Link; Lipase; Lipids; Lipoatrophy; Lipolysis; Liver; Mediating; Metabolic syndrome; Metabolism; Molecular; Mus; Names; Nicotinic Acids; Pathogenesis; Pathway interactions; Patients; Play; Principal Investigator; Production; Proteins; Regulation; Research; Role; Signal Transduction; Supplementation; Testing; Triglycerides; Up-Regulation; Zinc; Zinc deficiency; alcohol exposure; attenuation; deprivation; fatty acid transport; feeding; problem drinker; programs; public health relevance; receptor; sterol esterase; translocase; uptake

DESCRIPTION (provided by applicant): Adipose tissue lipolysis and alcoholic fatty liver Project Summary Alcoholic fatty liver is one of the earliest pathological changes in the progression of alcoholic liver disease. Accumulation of lipid in the hepatocyte makes the liver susceptible to inflammatory mediators or other toxic agents, leading to further progression to hepatitis and eventually fibrosis. Therefore, lipid accumulation is one of the most fundamental cellular disorders in alcoholic liver disease, and reduction of liver fat would likely halt or slow the progression of alcoholic liver disease. While alcohol induces fat accumulation in the liver, a significant decrease in fat mass (lipoatrophy) has been documented in chronic alcoholism. Our preliminary studies demonstrated a negative correlation between adipose tissue mass and liver fat in mice chronically fed alcohol. We also found that attenuation of alcoholic fatty liver by zinc supplementation is accompanied by partial reversal of lipoatrophy, suggesting a link between lipoatrophy and alcoholic fatty liver. Our recent studies further demonstrated that alcohol exposure upregulated hepatic fatty acid transporter 5 (FATP5) and CD36 (also named fatty acid translocase), suggesting an increased fatty acid uptake in the liver. On the other hand, chronic alcohol exposure activated both hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) pathways in the adipose tissue, indicating an upregulation of lipolysis. Our overall hypothesis is that reverse fatty acid transport due to excess lipolysis of the adipose tissue plays a crucial role in pathogenesis of alcoholic fatty liver. To test this hypothesis, four specific aims are proposed. Aim 1 is to determine if increased fatty acid uptake plays a crucial role in the development of alcoholic fatty liver. We will first document alcohol- induced increase in hepatic fatty acid uptake. We will then determine if blocking fatty acid uptake leads to reduction of alcoholic fatty liver. Aim 2 is to determine if excess lipolysis of the adipose tissue is a causal factor in alcohol-increased hepatic fatty acid uptake. We will first determine if alcohol exposure can enhance hepatic deposition of fatty acids mobilized from adipose tissue. We will then determine if blocking adipose tissue fatty acid mobilization can lead to attenuation of alcoholic fatty liver. Aim 3 is to investigate the molecular mechanisms by which alcohol induces excess lipolysis of the adipose tissue. We will first determine how alcohol exposure affects the lipolytic pathways in the adipose tissue. We will then define the role of nicotinic acid deficiency in HSL activation and the role of glucocorticoid in activation of ATGL lipolytic pathway. Aim 4 is to define the role of zinc in the regulation of adipose tissue lipolysis. We will first determine the effects of dietary zinc on lipolytic pathways and nicotinic acid metabolism and glucocorticoid production. We will then determine how zinc affects lipolytic signaling transduction in the adipocytes. PUBLIC HEALTH RELEVANCE: Alcoholic fatty liver is the earliest pathological change in the progression of alcoholic liver disease, but the mechanisms by which alcohol causes hepatic lipid accumulation have not been well defined. Clinical studies have shown a significant decrease in fat mass in patients with alcoholic fatty liver. Our preliminary studies demonstrated a negative correlation between liver fat and adipose tissue mass. We also found that alcohol exposure stimulates adipose tissue lipolysis and hepatic fatty acid uptake. This project will test our hypothesis that reverse fatty acid transport due to excess lipolysis of the adipose tissue plays a crucial role in the pathogenesis of alcoholic fatty liver.

描述（申请人提供）：脂肪组织脂解与酒精性脂肪肝 项目概要 酒精性脂肪肝是酒精性肝病进展中最早的病理变化之一。肝细胞中脂质的积累使肝脏容易受到炎症介质或其他有毒物质的影响，导致进一步发展为肝炎并最终导致纤维化。因此，脂质积累是酒精性肝病最基本的细胞紊乱之一，减少肝脏脂肪可能会阻止或减缓酒精性肝病的进展。虽然酒精会引起肝脏脂肪堆积，但慢性酒精中毒时脂肪量显着减少（脂肪萎缩）。我们的初步研究表明，长期喂食酒精的小鼠的脂肪组织质量和肝脏脂肪之间存在负相关。我们还发现，通过补充锌来减轻酒精性脂肪肝伴随着脂肪萎缩的部分逆转，这表明脂肪萎缩和酒精性脂肪肝之间存在联系。我们最近的研究进一步表明，酒精暴露会上调肝脏脂肪酸转运蛋白 5 (FATP5) 和 CD36（也称为脂肪酸转位酶），表明肝脏中脂肪酸的摄取增加。另一方面，长期接触酒精会激活脂肪组织中的激素敏感性脂肪酶（HSL）和脂肪甘油三酯脂肪酶（ATGL）途径，表明脂肪分解作用上调。我们的总体假设是，由于脂肪组织过度脂解而导致的反向脂肪酸转运在酒精性脂肪肝的发病机制中起着至关重要的作用。为了检验这一假设，提出了四个具体目标。目标 1 是确定脂肪酸摄取增加是否在酒精性脂肪肝的发展中起着至关重要的作用。我们将首先记录酒精引起的肝脂肪酸摄取增加。然后我们将确定阻断脂肪酸摄取是否会导致酒精性脂肪肝的减少。目标 2 是确定脂肪组织的过度脂解是否是酒精增加肝脏脂肪酸摄取的原因。我们将首先确定酒精暴露是否会增强从脂肪组织动员的脂肪酸的肝脏沉积。然后我们将确定阻断脂肪组织脂肪酸动员是否可以导致酒精性脂肪肝的减轻。目标 3 是研究酒精诱导脂肪组织过度脂解的分子机制。我们将首先确定酒精暴露如何影响脂肪组织中的脂肪分解途径。然后我们将定义烟酸缺乏在 HSL 激活中的作用以及糖皮质激素在 ATGL 脂解途径激活中的作用。目标 4 是明确锌在调节脂肪组织脂解作用中的作用。我们将首先确定膳食锌对脂肪分解途径、烟酸代谢和糖皮质激素产生的影响。然后我们将确定锌如何影响脂肪细胞中的脂肪分解信号转导。 公共卫生相关性：酒精性脂肪肝是酒精性肝病进展中最早的病理变化，但酒精导致肝脏脂质堆积的机制尚未明确。临床研究表明，酒精性脂肪肝患者的脂肪量显着减少。我们的初步研究表明肝脏脂肪和脂肪组织质量之间呈负相关。我们还发现酒精暴露会刺激脂肪组织脂肪分解和肝脏脂肪酸摄取。该项目将检验我们的假设，即由于脂肪组织过度脂解而导致的逆转脂肪酸转运在酒精性脂肪肝的发病机制中起着至关重要的作用。