Role of PNPLA3 in Fatty Liver Disease

PNPLA3 在脂肪肝疾病中的作用

基本信息

批准号：
8906845
负责人：
Helen Haskell Hobbs
金额：
$ 34.58万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8906845
关键词：
Address Adipocytes Adult Affect Alcoholic Fatty Liver Alcoholic Liver Diseases Alkaline Phosphatase American Society of Hematology Animal Model Animals Apolipoproteins B Biochemical Biochemistry Biological Biopsy Catabolism Cell Culture Techniques Child Chylomicrons Cirrhosis Data Diagnosis Disease Disease Progression Employee Strikes Fatty Liver Fatty acid glycerol esters Funding Genes Genetic Variation Goals Grant Health Hepatic Hepatocyte High Prevalence Hispanics Human Human Genetics Hypertriglyceridemia In Vitro Individual Inflammation Inflammatory Response Injury to Liver Intestines Isotope Labeling Life Link Lipase Lipids Lipoproteins Liver Liver Function Tests Liver diseases Low-Density Lipoproteins Malignant neoplasm of liver Mass Spectrum Analysis Metabolic Metabolic Pathway Metabolic syndrome Methodology Missense Mutation Modeling Molecular Mus Natural History Pathogenesis Phospholipase Physiological Physiology Plasma Play Predisposition Prevalence Primary carcinoma of the liver cells Proteins Proteome Reagent Role Serum Steatohepatitis Testing Therapeutic Therapeutic Intervention Triglycerides United States Variant base cofactor disease phenotype gene function genetic risk factor genetic variant homologous recombination human disease improved in vivo insight liver injury loss of function mouse model mutant non-alcoholic non-alcoholic fatty liver nonalcoholic steatohepatitis novel strategies prevent problem drinker progression marker research clinical testing research study small hairpin RNA therapy development

项目摘要

DESCRIPTION (provided by applicant): Fatty liver disease (FLD) is a burgeoning health problem that affects one-third of adults and an increasing number of children in the U.S. The two most common forms of FLD are nonalcoholic liver disease (NAFLD) and alcoholic liver disease (ALD). Both disorders begin with accumulation of triglyceride (TG) in the liver (steatosis), which in some individuals elicits an inflammatory response [nonalcoholic steatohepatitis (NASH) or alcoholic steatosis (ASH)] that can progress to cirrhosis and liver cancer. Therapeutic options to arrest disease progression in both disorders are very limited. The development of treatments for FLD has been hampered by limited appreciation of the molecular underpinnings of the disease, the lack of noninvasive markers of disease progression in humans, and a paucity of animal models that accurately recapitulate the pathogenesis of human FLD. As a first step to address these obstacles, our group used human genetics to identify genes that contribute to FLD. We identified a missense mutation (I148M) in patatin-like phospholipase domain-containing protein, PNPLA3, which is strongly associated with both hepatic TG content and inflammation. We showed that the variant is very frequent in Hispanics, who have the highest prevalence of NAFLD in the United States. Over 50 independent studies have confirmed and extended our findings to show that PNPLA3-I148M is enriched in individuals with biopsy-proven steatohepatitis, cirrhosis, and hepatocellular carcinoma both due to ALD and NAFLD. Thus, PNPLA3 is implicated as a contributing factor in the full spectrum of both NAFLD and ALD, suggesting that these two forms of FLD share not only pathological features but also molecular mechanisms in common. Recently, we identified a genetic variant in a second gene, TM6SF2, that confers susceptibility to both steatosis and inflammation. A missense variant in this gene is associated with increased hepatic TG content independently of PNPLA3. The function of this gene is unknown. In this application we will use a combination of classical biochemistry and physiology plus state-of-the-art mass spectrometry in mice with genetically-defined changes in PNPLA3 and TM6SF2 function to elucidate the physiological roles of these two proteins and the molecular mechanisms by which they promote hepatic fat accumulation and inflammation. We will leverage these findings to develop mouse models that more accurately recapitulate human NAFLD and ALD and provide improved reagents for pre-clinical testing. RELEVANCE: By elucidating the biological roles of PNPLA3 and TM6SF2 and the mechanisms by which variants in these proteins confer susceptibility to FLD, the experiments outlined in this proposal will provide new insights into the pathogenesis of a major human disease that continues to increase in prevalence. Our ultimate goal is to develop new approaches and strategies to diagnose, prevent, and treat FLD.

描述（由申请人提供）：脂肪肝病 (FLD) 是一种新兴的健康问题，影响着美国三分之一的成年人和越来越多的儿童。最常见的两种 FLD 形式是非酒精性肝病 (NAFLD) 和酒精性肝病肝病（ALD）。这两种疾病都始于肝脏中甘油三酯 (TG) 的积累（脂肪变性），这在某些个体中会引起炎症反应 [非酒精性脂肪性肝炎 (NASH) 或酒精性脂肪变性 (ASH)]，可进展为肝硬化和肝癌。阻止这两种疾病进展的治疗选择非常有限。由于对该疾病的分子基础了解有限、缺乏人类疾病进展的非侵入性标志物以及缺乏准确概括人类 FLD 发病机制的动物模型，FLD 治疗方法的开发受到阻碍。作为解决这些障碍的第一步，我们的团队利用人类遗传学来识别导致 FLD 的基因。我们在含有 patatin 样磷脂酶结构域的蛋白 PNPLA3 中发现了一个错义突变 (I148M)，该突变与肝脏 TG 含量和炎症密切相关。我们发现，这种变异在西班牙裔人群中非常常见，他们是美国 NAFLD 患病率最高的人群。超过 50 项独立研究证实并扩展了我们的研究结果，表明 PNPLA3-I148M 在经活检证实的 ALD 和 NAFLD 引起的脂肪性肝炎、肝硬化和肝细胞癌个体中富集。因此，PNPLA3 被认为是 NAFLD 和 ALD 的全谱中的一个促成因素，表明这两种形式的 FLD 不仅具有共同的病理特征，而且具有共同的分子机制。最近，我们在第二个基因 TM6SF2 中发现了一个遗传变异，它使人对脂肪变性和炎症具有易感性。该基因中的错义变异与肝脏 TG 含量增加相关，与 PNPLA3 无关。该基因的功能尚不清楚。在此应用中，我们将结合经典生物化学和生理学以及最先进的质谱分析技术，对 PNPLA3 和 TM6SF2 功能发生遗传性改变的小鼠进行分析，以阐明这两种蛋白质的生理作用以及其分子机制。它们促进肝脏脂肪堆积和炎症。我们将利用这些发现开发小鼠模型，更准确地再现人类 NAFLD 和 ALD，并为临床前测试提供改进的试剂。相关性：通过阐明 PNPLA3 和 TM6SF2 的生物学作用以及这些蛋白质的变异赋予 FLD 易感性的机制，本提案中概述的实验将为了解流行率持续增加的主要人类疾病的发病机制提供新的见解。我们的最终目标是开发新的方法和策略来诊断、预防和治疗 FLD。