Effects of TM6SF2 E167K on hepatic lipid and very low-density lipoprotein metabolism in humans
Effects of TM6SF2 E167K on hepatic lipid and very low-density lipoprotein metabolism in humans
复制标题
DOI：
10.1172/jci.insight.144079
复制
发表时间：
2020-12-17
期刊：
影响因子：
8
通讯作者：
Taskinen, Marja-Riitta
中科院分区：
文献类型：
--
作者：
Boren, Jan;Adiels, Martin;Taskinen, Marja-Riitta
非酒精性脂肪性肝病（NAFLD）的特征是肝脏脂质蓄积。跨膜6超家族成员2（TM 6SF 2）E167 K遗传变异与NAFLD和人类血浆甘油三酯水平降低相关。然而，这些关联的分子机制仍不清楚。我们假设TM 65 F2 E167 K影响肝脏极低密度脂蛋白（VLDL）的分泌，并研究了载脂蛋白13100（apoB 100）的动力学和甘油三酯代谢的VLDL在纯合子受试者。在10个纯合子TM 6SF 2 E167 K携带者和10个匹配的对照中，我们采用稳定同位素示踪和房室模型技术来确定apoB 100和甘油三酯动力学在2个主要的VIOL消减中：大的富含甘油三酯的VLDL和较小的，不富含甘油三酯的VLDL 2。TM 6SF 2 E167 K纯合子携带者VLDL 1-apoB 100的表达明显低于对照组。我也是TMSSF 2 E167 K携带者的VLDL-甘油三酯产生降低35%。相反，VLDL 2 apo 13100和甘油三酯的直接产生率在携带者和对照之间没有差异。总之，TM 6SF 2 E167 K遗传变异与肝脏分泌的富含大环内酯的VLDL 1的特异性减少有关。VLDL 1分泌受损解释了血浆甘油三酯浓度降低，并为理解与TM 6SF 2 E167 K遗传变异相关的心血管疾病风险降低提供了基础。
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation. The transmembrane 6 superfamily member 2 (TM6SF2) E167K genetic variant associates with NAFLD and with reduced plasma triglyceride levels in humans. However, the molecular mechanisms underlying these associations remain unclear. We hypothesized that TM65F2 E167K affects hepatic very low-density lipoprotein (VLDL) secretion and studied the kinetics of apolipoprotein 13100 (apoB100) and triglyceride metabolism in VLDL in homozygous subjects. In 10 homozygote TM6SF2 E167K carriers and 10 matched controls, we employed stable-isotope tracer and compartmental modeling techniques to determine apoB100 and triglyceride kinetics in the 2 major VIOL subtractions: large triglyceride-rich VLDL, and smaller, less triglyceride-rich VLDL2. VLDL1-apoB100 production was markedly reduced in homozygote TM6SF2 E167K carriers compared with controls. Likewise. VLDL,-triglyceride production was 35% lower in the TMSSF2 E167K carriers. In contrast, the direct production rates for VLDL2 apo13100 and triglyceride were not different between carriers and controls. In conclusion, the TM6SF2 E167K genetic variant was linked to a specific reduction in hepatic secretion of large triglyceride-rich VLDL1. The impaired secretion of VLDL1 explains the reduced plasma triglyceride concentration and provides a basis for understanding the lower risk of cardiovascular disease associated with the TM6SF2 E167K genetic variant.