The pathophysiological function of PNPLA3-148M variant in alcohol-induced liver injury

项目摘要 酒精相关性肝病（ALD）是饮酒者中非常常见的健康问题。多 全基因组关联研究已经可重复地鉴定了单核苷酸多态性（rs738409， 人马铃薯糖蛋白样磷脂酶结构域3（PNPLA3）基因中的C→G），其产生异亮氨酸 (I)氨基酸148处的甲硫氨酸（M）取代，作为与广泛的 ALD的范围从脂肪变性、肝炎到肝硬化。PNPLA3是一种脂滴相关的 在人类肝脏中表达最丰富的蛋白质，已显示具有甘油三酯脂肪酶， 棕榈酸视黄酯水解酶活性。然而，在肝脏中PNPLA3的148M变体的病理生理学 仍然很不清楚。在这个项目中，我们已经开发了两种人类基因变体的转基因小鼠模型， PNPLA3的表达，并在148M小鼠模型中验证了人ALD的关键特征。我们的目标是进一步解决 酒精诱导的肝脏炎症和纤维化中148M突变的分子基础， 细胞和动物模型。预期在此应用中的机理研究将提供直接的 148M变异体与相关肝脏病理学之间因果关系的证据。委员会共 我相信这个项目是非常有意义和创新的。

Project Summary Alcohol-related liver disease (ALD) is a very common health problem among alcohol drinkers. Multiple genome-wide association studies have reproducibly identified a single nucleotide polymorphism (rs738409, C→G) in the human patatin-like phospholipase domain containing 3 (PNPLA3) gene, which results in isoleucine (I) to methionine (M) substitution at amino acid 148, as the most significant gene variant associated with a broad spectrum of ALD ranging from steatosis, hepatitis, to cirrhosis to date. PNPLA3 is a lipid droplet-associated protein that is most abundantly expressed in human liver, which has been shown to have triglyceride lipase and retinyl palmitate hydrolase activities. However, the pathophysiology of the 148M variant of PNPLA3 in the liver remains largely unclear. In this project, we have developed transgenic mouse models for both variants of human PNPLA3 and validated the key features of human ALD in the 148M mouse model. We aim to further address the molecular underpinning of the 148M mutation in the alcohol-induced hepatic inflammation and fibrosis using both cell and animal models. It is expected that the mechanistic investigation in this application will provide direct evidence of the causal relationship between the 148M variant and the associated liver pathology. Altogether, we believe that this project is highly significant and innovative.