Targeted deletion of fatty acid transport protein-4 results in early embryonic lethality
Targeted deletion of fatty acid transport protein-4 results in early embryonic lethality
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DOI：
10.1074/jbc.m309759200
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发表时间：
2003-12-05
影响因子：
4.8
通讯作者：
Stahl, A
中科院分区：
文献类型：
--
作者：
Gimeno, RE;Hirsch, DJ;Stahl, A
脂肪酸转运蛋白4（FATP 4）是小肠中的主要FATP。我们先前使用体外反义实验证明，FATP 4是肠上皮细胞摄取脂肪酸所必需的。为了进一步研究FATP 4的生理作用，产生了携带FATP 4靶向缺失的小鼠。FATP 4的一个等位基因的缺失导致FATP 4蛋白水平降低48%，分离的肠上皮细胞的脂肪酸摄取降低40%。然而，一个FATP 4等位基因的丢失对正常或高脂肪饮食的脂肪吸收没有任何可检测的影响。两个FATP 4等位基因的缺失导致胚胎致死，因为杂合FATP 4亲本之间的杂交导致没有纯合后代;此外，早在妊娠第9.5天就没有检测到纯合胚胎。已观察到与小肠中脂质吸收相关的其他基因（即微粒体甘油三酯转移蛋白和载脂蛋白B）缺失的早期胚胎致死性，并已将其归因于胚胎发育早期跨越内脏内胚层的脂肪吸收要求。在小鼠中，胚外内胚层在绒毛尿囊胎盘发育之前为胚胎提供营养。在野生型小鼠中，我们发现FATP 4蛋白由内脏内胚层的上皮细胞高度表达，并定位于胚外内胚层细胞的刷状缘膜。这种定位与FATP 4在早期胚胎发生中脂肪吸收的作用一致，并表明在发育过程中对FATP 4功能的新要求。
Fatty acid transport protein-4 (FATP4) is the major FATP in the small intestine. We previously demonstrated, using in vitro antisense experiments, that FATP4 is required for fatty acid uptake into intestinal epithelial cells. To further examine the physiological role of FATP4, mice carrying a targeted deletion of FATP4 were generated. Deletion of one allele of FATP4 resulted in 48% reduction of FATP4 protein levels and a 40% reduction of fatty acid uptake by isolated enterocytes. However, loss of one FATP4 allele did not cause any detectable effects on fat absorption on either a normal or a high fat diet. Deletion of both FATP4 alleles resulted in embryonic lethality as crosses between heterozygous FATP4 parents resulted in no homozygous offspring; furthermore, no homozygous embryos were detected as early as day 9.5 of gestation. Early embryonic lethality has been observed with deletion of other genes involved in lipid absorption in the small intestine, namely microsomal triglyceride transfer protein and apolipoprotein B, and has been attributed to a requirement for fat absorption early in embryonic development across the visceral endoderm. In mice, the extraembryonic endoderm supplies nutrients to the embryo prior to development of a chorioallantoic placenta. In wild-type mice we found that FATP4 protein is highly expressed by the epithelial cells of the visceral endoderm and localized to the brush-border membrane of extraembryonic endodermal cells. This localization is consistent with a role for FATP4 in fat absorption in early embryogenesis and suggests a novel requirement for FATP4 function during development.