Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids
Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids
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DOI：
10.1172/jci.insight.127902
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发表时间：
2019-08-22
期刊：
影响因子：
8
通讯作者：
Yki-Javinen, Hannele
中科院分区：
文献类型：
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作者：
Luukkonen, Panu K.;Nick, Auli;Yki-Javinen, Hannele
常见的马铃薯糖样磷脂酶结构域蛋白3（PNPLA 3）变体I148 M易患非酒精性肝病，但不是其代谢后遗症。我们比较了标记的多不饱和脂肪酸（PUFAs）和饱和脂肪酸（SFA）在人体内和细胞中携带不同PNPLA 3基因型的处理。在148 M纯合子个体中，与148 I纯合子相比，空腹和餐后条件下极低密度脂蛋白（VIOL）中的甘油三酯（TG）中的PUFA均被耗尽，并且VLDL-TG中的PUFA/SFA比率相对于乳糜微粒前体池较低。在人PNPLA 3 - 148 M和PNPLA 3-KO细胞中，以磷脂酰胆碱为代价增加了PUFA而不是SFA掺入TG，并且在脂解条件下，与PNPLA 3 - 148 I细胞相比，含有PUFA的二酰基甘油（DAG）积累。与148 I纯合子相比，148 M纯合子的人肝脏中多不饱和TG增加，而磷脂酰胆碱（PC）减少。我们的结论是，人类PNPLA 3-I148 M是一个功能丧失的等位基因，通过损害水解/转酰PUFA从DAG饲料磷脂酰胆碱合成的多不饱和方向重塑肝脏TG。
The common patatin-like phospholipase domain-containing protein 3 (PNPLA3) variant I148M predisposes to nonalcoholic liver disease but not its metabolic sequelae. We compared the handling of labeled polyunsaturated fatty acids (PUFAs) and saturated fatty acids (SFA) in vivo in humans and in cells harboring different PNPLA3 genotypes. In 148M homozygous individuals, triglycerides (TGs) in very low-density lipoproteins (VIOL) were depleted of PUFAs both under fasting and postprandial conditions compared with 148I homozygotes, and the PUFA/SFA ratio in VLDL-TGs was lower relative to the chylomicron precursor pool. In human PNPLA3-148M and PNPLA3-KO cells, PUFA but not SFA incorporation into TGs was increased at the expense of phosphatidylcholines, and under lipolytic conditions, PUFA-containing diacylglycerols (DAGs) accumulated compared with PNPLA3-148I cells. Polyunsaturated TGs were increased, while phosphatidylcholines (PCs) were decreased in the human liver in 148M homozygous individuals as compared with 148I homozygotes. We conclude that human PNPLA3-I148M is a loss-of-function allele that remodels liver TGs in a polyunsaturated direction by impairing hydrolysis/transacylation of PUFAs from DAGs to feed phosphatidylcholine synthesis.