Department of Pathophysiology and Transplantation, section Internal Medicine, Università degli Studi Milano, UO Medicina Interna1B, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy.
Curr Pharm Des. 2013;19(29):5219-38. doi: 10.2174/13816128113199990381.
Liver fat deposition related to systemic insulin resistance defines non-alcoholic fatty liver disease (NAFLD) which, when associated with oxidative hepatocellular damage, inflammation, and activation of fibrogenesis, i.e. non-alcoholic steatohepatitis (NASH), can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease and the leading cause of altered liver enzymes in Western countries. Epidemiological, familial, and twin studies provide evidence for an element of heritability of NAFLD. Genetic modifiers of disease severity and progression have been identified through genome-wide association studies. These include the Patatin-like phosholipase domain-containing 3 (PNPLA3) gene variant I148M as a major determinant of inter-individual and ethnicity-related differences in hepatic fat content independent of insulin resistance and serum lipid concentration. Association studies confirm that the I148M polymorphism is also a strong modifier of NASH and progressive hepatic injury. Furthermore, a few large multicentre case-control studies have demonstrated a role for genetic variants implicated in insulin signalling, oxidative stress, and fibrogenesis in the progression of NAFLD towards fibrosing NASH, and confirm that hepatocellular fat accumulation and insulin resistance are key operative mechanisms closely involved in the progression of liver damage. It is now important to explore the molecular mechanisms underlying these associations between gene variants and progressive liver disease, and to evaluate their impact on the response to available therapies. It is hoped that this knowledge will offer further insights into pathogenesis, suggest novel therapeutic targets, and could help guide physicians towards individualised therapy that improves clinical outcome.
与全身胰岛素抵抗相关的肝脂肪沉积定义了非酒精性脂肪性肝病（NAFLD），当它与氧化肝细胞损伤、炎症和纤维化激活（即非酒精性脂肪性肝炎[NASH]）相关时，可能会进展为肝硬化和肝细胞癌。由于肥胖症的流行，NAFLD 现在是最常见的肝脏疾病，也是西方国家肝酶改变的主要原因。流行病学、家族和双胞胎研究为 NAFLD 的遗传因素提供了证据。通过全基因组关联研究已经确定了疾病严重程度和进展的遗传修饰因子。这些包括富含 patatin 样磷酸酶结构域 3（PNPLA3）基因的 I148M 变体，它是个体间和种族相关肝脂肪含量差异的主要决定因素，而与胰岛素抵抗和血清脂质浓度无关。关联研究证实，I148M 多态性也是 NASH 和进行性肝损伤的主要修饰因子。此外，一些大型多中心病例对照研究表明，胰岛素信号、氧化应激和纤维化形成中涉及的遗传变异在 NAFLD 向纤维化 NASH 的进展中起作用，并证实肝细胞脂肪堆积和胰岛素抵抗是密切参与肝损伤进展的关键操作机制。现在重要的是探索这些基因变异与进行性肝病之间的关联的分子机制，并评估它们对现有治疗方法的反应的影响。希望这些知识将为发病机制提供进一步的见解，提出新的治疗靶点，并有助于指导医生进行个体化治疗，改善临床结局。
