Università degli Studi Milano, Policlinico MaRE IRCCS Hospital, Milan, Italy.
Gut. 2010 Feb;59(2):267-73. doi: 10.1136/gut.2009.190801.
BACKGROUND/AIMS: The aim of this study was to assess the effect of functional ENPP1(ectoenzyme nucleotide pyrophosphate phosphodiesterase 1)/PC-1 (plasma cell antigen-1) and IRS-1 (insulin receptor substrate-1) polymorphisms influencing insulin receptor activity on liver damage in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, whose progression is associated with the severity of insulin resistance.
702 patients with biopsy-proven NAFLD from Italy and the UK, and 310 healthy controls. The Lys121Gln ENPP1/PC-1 and the Gly972Arg IRS-1 polymorphisms were evaluated by restriction analysis. Fibrosis was evaluated according to Kleiner. Insulin signalling activity was evaluated by measuring phosphoAKT levels by western blotting in a subset of obese non-diabetic patients.
The ENPP1 121Gln and IRS-1 972Arg polymorphisms were detected in 28.7% and 18.1% of patients and associated with increased body weight/dyslipidaemia and diabetes risk, respectively. The ENPP1 121Gln allele was significantly associated with increased prevalence of fibrosis stage >1 and >2, which was higher in subjects also positive for the 972Arg IRS-1 polymorphism. At multivariate analysis, the presence of the ENPP1 121Gln and IRS-1 972Arg polymorphisms was independently associated with fibrosis >1 (OR 1.55, 95% CI 1.24 to 1.97; and OR 1.57, 95% CI 1.12 to 2.23, respectively). Both polymorphisms were associated with a marked reduction of approximately 70% of AKT activation status, reflecting insulin resistance and disease severity, in obese patients with NAFLD.
The ENPP1 121Gln and IRS-1 972Arg polymorphisms affecting insulin receptor activity predispose to liver damage and decrease hepatic insulin signalling in patients with NAFLD. Defective insulin signalling may play a causal role in the progression of liver damage in NAFLD.
背景/目的：本研究旨在评估影响胰岛素受体活性的功能性 ENPP1（外核苷酸焦磷酸酶/磷酸二酯酶 1）/PC-1（浆细胞抗原-1）和 IRS-1（胰岛素受体底物-1）多态性对非酒精性脂肪性肝病（NAFLD）肝脏损伤的影响，NAFLD 是代谢综合征的肝脏表现，其进展与胰岛素抵抗的严重程度相关。
来自意大利和英国的 702 名经活检证实的 NAFLD 患者和 310 名健康对照者。通过限制性分析评估 Lys121Gln ENPP1/PC-1 和 Gly972Arg IRS-1 多态性。根据 Kleiner 评估纤维化。在肥胖非糖尿病患者的亚组中，通过 Western 印迹法测量磷酸化 AKT 水平来评估胰岛素信号转导活性。
在 28.7%和 18.1%的患者中检测到 ENPP1 121Gln 和 IRS-1 972Arg 多态性，分别与体重增加/血脂异常和糖尿病风险增加相关。ENPP1 121Gln 等位基因与纤维化程度 >1 和 >2 的患病率显著增加相关，在同时携带 IRS-1 972Arg 多态性的患者中更高。多变量分析显示，ENPP1 121Gln 和 IRS-1 972Arg 多态性的存在与纤维化 >1（OR 1.55，95%CI 1.24 至 1.97；OR 1.57，95%CI 1.12 至 2.23）独立相关。在肥胖的 NAFLD 患者中，这两种多态性均与 AKT 激活状态的显著降低（约 70%）相关，反映了胰岛素抵抗和疾病严重程度。
影响胰岛素受体活性的 ENPP1 121Gln 和 IRS-1 972Arg 多态性易导致 NAFLD 患者的肝脏损伤，并降低肝脏胰岛素信号。胰岛素信号的缺陷可能在 NAFLD 肝脏损伤的进展中起因果作用。
