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）是一个新兴的健康问题，影响了成年人的三分之一，而在美国，FLD的两种最常见的FLD形式是非酒精性肝病（NAFLD）和酒精性肝病（ALD）。两种疾病都始于肝脏（脂肪变性）中甘油三酸酯（TG）的积累，在某些人中，这会引起炎症反应[非酒精性脂肪性肝炎（NASH）或酒精脂肪变性（ASH）]，可以发展为cirrhosis和cirrhosis和肝癌。在两种疾病中阻止疾病进展的治疗选择非常有限。对疾病的分子基础，人类疾病进展的缺乏侵入性标志的浓度有限，对FLD治疗的发展受到了阻碍。作为解决这些障碍的第一步，我们的小组使用人类遗传学来识别有助于FLD的基因。我们确定了含patatin的磷脂酶域蛋白PNPLA3中的错义突变（I148M），这与肝TG含量和炎症都密切相关。我们表明，这种变体在西班牙裔中很频繁，他们在美国的患病率最高。超过50项独立研究已经证实并扩展了我们的发现，以表明PNPLA3-I148M在经过活检证实的脂肪性肝炎，肝硬化和肝细胞癌的个体中都富含由于ALD和NAFLD而导致的。因此，PNPLA3被认为是NAFLD和ALD的全部范围中的一个促成因素，这表明这两种形式的FLD不仅具有病理特征，而且具有共同的分子机制。最近，我们确定了第二个基因TM6SF2中的遗传变异，该变异既赋予了脂肪变性和炎症的易感性。该基因中的错义变体与肝TG含量增加有关，独立于PNPLA3。该基因的功能未知。在此应用中，我们将使用经典生物化学和生理学以及在PNPLA3和TM6SF2功能中具有遗传定义的变化的小鼠中的最先进的质谱法组合，以阐明这两种蛋白质的生理作用以及它们促进肝脂肪累积和炎症的分子机制。我们将利用这些发现来开发小鼠模型，这些模型更准确地概括了人类NAFLD和ALD，并为临床前测试提供了改进的试剂。相关性：通过阐明PNPLA3和TM6SF2的生物学作用以及这些蛋白质中赋予FLD敏感性的变异的机制，该提案中概述的实验将提供对主要人类疾病的发病机理的新见解，从而持续增长了预期。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。