Alcohol Intake and Hepatic Fat Metabolism

酒精摄入量和肝脏脂肪代谢

• 批准号: 8304200
• 负责人: LI-SHIN HUANG
• 金额: $ 19万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-20 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8304200
• 关键词: Ablation; Address; Adenoviruses; Adipose tissue; Affect; Alcohol consumption; Alcoholic Fatty Liver; Alcoholic Liver Diseases; Alcohols; Biochemical; Biochemistry; Blood; Carcinoma; Characteristics; Chronic; Cirrhosis; Data; Development; Diet; Disease; Drug Formulations; Elements; Enzymes; Etiology; Event; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Gene Targeting; Genes; Goals; Health; Hepatic; Hepatocyte; Hydrolase; Hydrolysis; Hyperlipidemia; Hypertension; Individual; Inflammation; Injury; Investigation; Laboratories; Lipase; Lipids; Liver; Liver diseases; Measures; Metabolic; Metabolic syndrome; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Oxidative Stress; PPAR alpha; Pathology; Peroxisome Proliferator-Activated Receptors; Physiological; Predisposition; Primary carcinoma of the liver cells; Proteins; Protocols documentation; Public Health; Publishing; Recombinants; Role; Staging; Steatohepatitis; Stress; Triglyceride Metabolism; Triglycerides; United States; Up-Regulation; Variant; Very low density lipoprotein; Work; alcohol prevention; chronic alcohol ingestion; diacylglycerol O-acyltransferase; effective intervention; experience; fatty acid oxidation; feeding; hepatic lipase; lipid biosynthesis; lipid metabolism; liquid chromatography mass spectrometry; liver function; mitochondrial dysfunction; mouse model; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; overexpression; oxidation; prevent; problem drinker; uptake

DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) is a serious public health problem in the US, and throughout the entire world. ALD results from chronic alcohol consumption and starts as simple steatosis, characterized by an over accumulation of lipid, primarily triglycerides (TG), in hepatocytes. A subset of subjects with simple steatosis progress to alcoholic steatohepatitis (ASH), which can further progress to fibrosis, eventually leading to cirrhosis and hepatoculluar carcinoma. The underlying general hypothesis for our studies is that the difference in susceptibility to ALD disease reflects individual variation in hepatic lipid metabolism. Since there are no direct treatments available for ALD, understanding better the mechanisms underlying alcoholic fatty liver development is crucial for developing effective interventions for blocking ALD. The overall goal of this application is to gain new understanding of the early events in ALD development. The specific hypothesis that will be addressed experimentally in this proposal is that dysregulated hepatic TG hydrolysis and dysregulated TG synthesis have important contributory roles in the development of alcoholic steatosis. Since a fatty liver by definition implies excessive hepatic TG accumulation, we are proposing to investigate the 2 most proximal metabolic steps associated with TG accumulation, TG synthesis and degradation. All of our studies will be carried out in mice and will involve chronic feeding, for 4 weeks, of either the alcohol-containing or the isocaloric alcohol-free control Leiber-DeCarli diet formulations. These studies will also make use of adenoviral expression or knockdown constructs for a number of hepatic lipases and TG synthesizing enzymes, as well as other experimental protocols and expertise gained in our earlier published studies of the role of lipases in diet-induced (high fat diet) hepatic steatosis. In Specific Aim 1, we propose to evaluate the roles that several different hepatic lipases may have in the development/prevention of alcohol-induced fatty liver. Although the great majority of experimental protocols needed for undertaking this Aim are well established in the PI's laboratory, there is an exploratory element to this Specific Aim since the normal physiological role of one of the four lipases proposed for study in Specific Aim 1 is not well established. Specific Aim 2 will explore the specific roles that diacylglycerol acyltransferase 1 and 2 (DGAT1 and DGAT2), the two genetically distinct hepatic enzymes that catalyze the final step of TG synthesis, have in the development of alcoholic fatty liver. Our preliminary data establish that both DGAT1 and DGAT2 expression are elevated, by approximately 2-fold, in livers of alcohol-fed mice. Investigations proposed in Specific Aim 2 will define the specific actions of DGAT1 and DGAT 2 in the early stages of ALD development.

描述（由申请人提供）：酒精性肝病（ALD）是美国乃至全世界的一个严重的公共卫生问题。 ALD 是由长期饮酒引起的，最初是简单的脂肪变性，其特征是肝细胞中脂质过度积累，主要是甘油三酯 (TG)。一部分患有单纯性脂肪变性的受试者会进展为酒精性脂肪性肝炎 (ASH)，后者可进一步进展为纤维化，最终导致肝硬化和肝癌。我们研究的基本假设是，ALD 疾病易感性的差异反映了肝脏脂质代谢的个体差异。由于 ALD 没有直接的治疗方法，因此更好地了解酒精性脂肪肝发展的机制对于制定有效的干预措施来阻止 ALD 至关重要。此应用程序的总体目标是获得对 ALD 发展早期事件的新认识。本提案将通过实验解决的具体假设是，肝脏 TG 水解失调和 TG 合成失调在酒精性脂肪变性的发展中具有重要的促进作用。由于脂肪肝的定义意味着肝脏 TG 积累过多，因此我们建议研究与 TG 积累、TG 合成和降解相关的 2 个最近的代谢步骤。我们所有的研究都将在小鼠身上进行，并涉及长期喂养含酒精或不含等热量酒精的 Leiber-DeCarli 饮食配方，持续 4 周。这些研究还将利用多种肝脂肪酶和 TG 合成酶的腺病毒表达或敲低构建体，以及我们之前发表的关于脂肪酶在饮食诱导（高脂肪饮食）中作用的研究中获得的其他实验方案和专业知识。 ）肝脂肪变性。在具体目标 1 中，我们建议评估几种不同的肝脂肪酶在酒精性脂肪肝的发生/预防中可能发挥的作用。尽管实现该目标所需的绝大多数实验方案均已在 PI 实验室中得到完善，但该特定目标仍具有探索性成分，因为特定目标 1 中提出研究的四种脂肪酶之一的正常生理作用尚不明确。已确立的。具体目标 2 将探讨二酰基甘油酰基转移酶 1 和 2（DGAT1 和 DGAT2）（这两种遗传上不同的肝酶，催化 TG 合成的最后一步）在酒精性脂肪肝发展中的具体作用。我们的初步数据表明，在酒精喂养的小鼠肝脏中，DGAT1 和 DGAT2 的表达均升高约 2 倍。具体目标 2 中提出的研究将定义 DGAT1 和 DGAT 2 在 ALD 发展早期阶段的具体行动。