The Kruppel-Like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease
The Kruppel-Like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease
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DOI：
10.1053/j.gastro.2008.04.004
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发表时间：
2008-07-01
期刊：
影响因子：
29.4
通讯作者：
Reeves, Helen L.
中科院分区：
文献类型：
--
作者：
Miele, Luca;Beale, Gary;Reeves, Helen L.
背景与目的：虽然非酒精性脂肪性肝病（NAFLD）越来越普遍，但只有少数患者发展为纤维化性肝病。基于其在肝脏生长和修复中的作用，我们探讨了kruppel样因子6 （KLF6）是否在NAFLD进展中起作用。方法：采用实时聚合酶链反应（real-time polymerase chain reaction）检测31例NAFLD肝活检组织中KLF6的表达。利用转染后的miniigene构建物研究了多态性KLF6- ivsi - 27g > a在体外促进KLF6选择性剪接的影响。我们对3组患者进行KLF6-IVS1-27G > A基因分型（英国组1，n = 306；意大利组2，n = 109；三人组3，n = 61名儿童和家长）。结果：KLF6表达的增加与NAFLD肝脏脂肪变性、炎症和纤维化的增加有关。KL.P6-IVSI-27G>A促进了KLF6的选择性剪接，并在LX-2细胞中抑制了A -平滑肌肌动蛋白和胶原蛋白1的上调。组1基因分型在306例中鉴定出44例KLF6-IVS1-27G>A(14.4%)的病人。值得注意的是，KLF6-IVS1-27G > A与轻度NAFLD显著相关，只有25%的患者有更严重的纤维化，而野生型（wt）患者的这一比例为45%。这一趋势在第二组得到证实。对所有415例患者进行线性回归分析，调整年龄、性别、体重指数和血糖水平，证实wt KLF6等位基因的存在是纤维化NAFLD的独立预测因子。此外，我们已经证明wt等位基因优先传播给患有纤维化NAFLD的儿童。结论：我们报道了与晚期NAFLD相关的YLF6基因的功能多态性，并相信对KLF6的进一步研究可能会增强我们对该疾病过程的理解。
Background&AiMS: Although nonalcoholic fatty liver disease (NAFLD) is increasingly common, only a minority of affected individuals develop fibrotic liver disease. Based on its role in liver growth and repair, we explored whether Kruppel-like factor 6 (KLF6) plays a role in NAFLD progression. Methods: KLF6 expression in 31 fibrosis scored NAFLD liver biopsy specimens was assessed by real-time polymerase chain reaction. Transfected minigene constructs were used to study the effect of a polymorphism, KLF6-IVSI-27G > A, that promotes KLF6 alternative splicing in vitro. We genotyped KLF6-IVS1-27G > A in 3 groups of patients (UK group 1, n = 306; Italian group 2, n = 109; trio group 3, n = 61 children and parents). Results: KLF6 expression was increased in association with increased steatosis, inflammation, and fibrosis in NAFLD livers. KL.P6-IVSI-27G>A promoted alternative splicing of KLF6 and abrogated the up-regulation of both a-smooth muscle actin and collagen 1 in LX-2 cells. Group 1 genotyping identified KLF6-IVS1-27G>A in 44 of.306 (14.4%) patients. Notably, KLF6-IVS1-27G > A was associated significantly with milder NAFLD, with only 25% having more advanced fibrosis compared with 45% of wildtype (wt) individuals. This trend was confirmed in group 2. A linear regression analysis including all 415 patients, adjusted for age, sex, body mass index, and blood glucose level, confirmed that presence of the wt KLF6 allele was an independent predictor of fibrotic NAFLD. Furthermore, we have shown preferential transmission of the wt allele to children with fibrotic NAFLD. Conclusions: We report a functional polymorphism in the YLF6 gene associated with advanced NAFLD and believe further study of KLF6 may enhance our understanding of this disease process.