Paola Dongiovanni, Benedetta Donati, Roberta Fares, Rosa Lombardi, Luca Valenti, Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milano, Italy.
World J Gastroenterol. 2013 Nov 7;19(41):6969-78. doi: 10.3748/wjg.v19.i41.6969.
The 148 Isoleucine to Methionine protein variant (I148M) of patatin-like phospholipase domain-containing 3 (PNPLA3), a protein is expressed in the liver and is involved in lipid metabolism, has recently been identified as a major determinant of liver fat content. Several studies confirmed that the I148M variant predisposes towards the full spectrum of liver damage associated with fatty liver: from simple steatosis to steatohepatitis and progressive fibrosis. Furthermore, the I148M variant represents a major determinant of progression of alcohol related steatohepatitis to cirrhosis, and to influence fibrogenesis and related clinical outcomes in chronic hepatitis C virus hepatitis, and possibly chronic hepatitis B virus hepatitis, hereditary hemochromatosis and primary sclerosing cholangitis. All in all, studies suggest that the I148M polymorphism may represent a general modifier of fibrogenesis in liver diseases. Remarkably, the effect of the I148M variant on fibrosis was independent of that on hepatic steatosis and inflammation, suggesting that it may affect both the quantity and quality of hepatic lipids and the biology of non-parenchymal liver cells besides hepatocytes, directly promoting fibrogenesis. Therefore, PNPLA3 is a key player in liver disease progression. Assessment of the I148M polymorphism will possibly inform clinical practice in the future, whereas the determination of the effect of the 148M variant will reveal mechanisms involved in hepatic fibrogenesis.
载脂蛋白 patatin 样磷脂酶域包含蛋白 3（PNPLA3）的 148 位异亮氨酸突变为蛋氨酸（I148M）的蛋白变体，该蛋白在肝脏中表达，参与脂质代谢，最近被确定为肝内脂肪含量的主要决定因素。几项研究证实，I148M 变体易患与脂肪肝相关的各种肝损伤：从单纯性脂肪变性到肝炎和进行性纤维化。此外，I148M 变体是酒精性脂肪性肝炎进展为肝硬化的主要决定因素，并影响慢性丙型肝炎病毒肝炎、可能的慢性乙型肝炎病毒肝炎、遗传性血色病和原发性硬化性胆管炎中的纤维化和相关临床结局。总而言之，研究表明，I148M 多态性可能代表肝脏疾病纤维化的一般修饰因子。值得注意的是，I148M 变体对纤维化的影响独立于对肝脂肪变性和炎症的影响，这表明它可能影响肝内脂质的数量和质量以及非实质细胞（除肝细胞外）的生物学特性，直接促进纤维化。因此，PNPLA3 是肝脏疾病进展的关键因素。评估 I148M 多态性可能会在未来告知临床实践，而确定 148M 变体的作用将揭示肝纤维化涉及的机制。
