Circulating triacylglycerol signatures and insulin sensitivity in NAFLD associated with the E167K variant in TM6SF2
Circulating triacylglycerol signatures and insulin sensitivity in NAFLD associated with the E167K variant in TM6SF2
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DOI：
10.1016/j.jhep.2014.10.010
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发表时间：
2015-03-01
影响因子：
25.7
通讯作者：
Yki-Jarvinen, Hannele
中科院分区：
文献类型：
--
作者：
Zhou, You;Llaurado, Gemma;Yki-Jarvinen, Hannele
背景与目的：最近发现跨膜6超家族成员2蛋白(TM6SF2)中的Glu167Lys(E167K)变异可影响肝脏脂肪含量。我们旨在研究这种变异如何影响循环中的三酰甘油(TAG)信号，以及它是否影响肝脏或脂肪组织的胰岛素敏感性。方法：我们对300名芬兰受试者TM6SF2的E167K(Rs58542926)变异和PNPLA3(PNPLA3)的I148M(Rs738409)变异进行了基因分型，并用H-1-MRS和UPLC-MS测定了LFAT。我们比较了E167K携带者(TM6SF2(EK/KK))和非携带者(TM6SF2(EE))以及三组NAFLD之间的血浆脂质体谱：(I)PNPLA3基因E167K但不携带I148M变异的携带者(‘TM6SF2 NAFLD’)，(Ii)携带I148M但不携带E167K变异的(‘PNPLA3 NAFLD’)，以及(Iii)任何一个危险等位基因的非携带者(‘非危险NAFLD’)。结果：TM6SF2(EK/KK)组LFAT含量(13.07+/-1.57%)高于TM6SF2(EE)组(9.77+/-0.58%，P=0.013)。TM6SF2(EK/KK)组胰岛素对葡萄糖生成和脂解的影响显著高于TM6SF2(EE)组。三组具有相似LFAT的NAFLD组的比较显示，TM6SF2 NAFLD和PNPLA3 NAFLD组的甘油三酯水平显著低于非危险NAFLD组，且最常见的标签水平低于非危险NAFLD组。结论：我们得出结论：TM6SF2的E167K变异与NAFLD的一个独特亚型有关，该亚型的特点是尽管LFAT含量明显增加，但对脂肪分解、肝脏葡萄糖产生和高甘油三酯血症的胰岛素敏感性保持不变。(C)2014年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background & Aims: The Glu167Lys (E167K) variant in the transmembrane 6 superfamily member 2 protein (TM6SF2) was recently shown to influence liver fat (LFAT) content. We aimed at studying how this variant influences circulating triacylglycerol (TAG) signatures and whether it influences hepatic or adipose tissue insulin sensitivity.Methods: We genotyped 300 Finnish subjects for the E167K (rs58542926) variant in TM6SF2 and for the I148M (rs738409) variant in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) in whom LFAT was measured using H-1-MRS and circulating lipids by UPLC-MS. We compared the plasma lipidome between E167K carriers (TM6SF2(EK/KK)) and non-carriers (TM6SF2(EE)), and between three groups of NAFLD: (i) carriers of the E167K but not of the I148M variant in PNPLA3 ('TM6SF2 NAFLD'), (ii) carriers of the I148M but not of the E167K variant ('PNPLA3 NAFLD'), and (iii) non-carriers of either risk allele ('Non-risk NAFLD'). Hepatic and adipose tissue insulin sensitivities were measured using the euglycemic hyperinsulinemic clamp technique combined with infusion of [3-H-3]glucose in 111 subjects.Results: The LFAT content was 34% higher in the TM6SF2(EK/KK) (13.07 +/- 1.57%) than in the TM6SF2(EE) group (9.77 +/- 0.58%, p = 0.013). The effect of insulin on glucose production and lipolysis were significantly higher in the TM6SF2(EK/KK) than in the TM6SF2(EE) group. Comparison of the three NAFLD groups with similar LFATs showed that both the 'TM6SF2 NAFLD' and 'PNPLA3 NAFLD' had significantly lower triglyceride levels and were characterized by lower levels of most common TAGs compared to the 'Non-risk NAFLD' group.Conclusions: We conclude that the E167K variant in TM6SF2 is associated with a distinct subtype of NAFLD, characterized by preserved insulin sensitivity with regard to lipolysis, hepatic glucose production and lack of hypertriglyceridemia despite a clearly increased LFAT content. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.