调控胰岛素受体信号的遗传变异与非酒精性脂肪性肝病患者肝损伤严重程度相关。
Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease.
机构信息
Università degli Studi Milano, Policlinico MaRE IRCCS Hospital, Milan, Italy.
出版信息
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.
PATIENTS AND METHODS
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.
RESULTS
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.
CONCLUSIONS
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。
患者和方法
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。
结果
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。
结论
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。
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