Tiebel O, Oka K, Robinson K, Sullivan M, Martinez J, Nakamuta M, Ishimura-Oka K, Chan L
Department of Cell Biology and Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Atherosclerosis. 1999 Aug;145(2):239-51. doi: 10.1016/s0021-9150(99)00068-4.
The very low density lipoprotein receptor (VLDLR) is a multifunctional apolipoprotein (apo) E receptor that shares a common structural feature as well as some ligand specificity to apo E with members of the low density lipoprotein receptor gene family. We have isolated and characterized the mouse VLDLR gene. The mouse VLDLR gene contains 19 exons spanning approximately 50 kb. The exon-intron organization of the gene is completely conserved between mouse and human. Since the 5'-flanking region of the mouse VLDLR gene contains two copies of a sterol regulatory element-1 like sequence (SRE-1), we next studied regulation of the VLDLR mRNA expression in heart, skeletal muscle and adipose tissue in C57BL/6, LDLR-/-, apo E-/- and LDLR-/-apo E-/- mice fed normal chow or atherogenic diet. The VLDLR mRNA expression was down-regulated 3-fold by feeding atherogenic diet in heart and skeletal muscle only in LDLR-/- mice. In contrast, VLDLR mRNA expression was up-regulated by atherogenic diet in adipose tissue in all animal models except double knockout mice. These results suggest that SRE-1 may be functional and VLDLR plays a role in cholesterol homeostasis in heart and skeletal muscle when LDLR is absent and that apo E is required for this modulation. Developmental regulation of the VLDLR mRNA expression was also tissue-specific. VLDLR mRNA expression in heart displayed significant up and down regulation during development. Maximal level was detected on post-natal day 3. However, the VLDLR mRNA levels in skeletal muscle remained relatively constant except a slight dip on post-natal day 7. In kidney and brain, VLDLR mRNA also peaked on post-natal day 3 but remained relatively constant thereafter. In liver, VLDLR mRNA expression was very low; it was barely detectable at day 19 of gestation and was decreased further thereafter. In adipose tissue, the VLDLR mRNA level showed an increase on post-natal day 13, went down again during weaning and then continued to increase afterwards. This developmental pattern as well as dietary regulation in adipose tissue supports the notion that VLDLR plays a role in lipid accumulation in this tissue. Although the primary role of VLDLR in heart, muscle and adipose tissue is likely in lipid metabolism, developmental pattern of this receptor in other tissues suggests that VLDLR has functions that are unrelated to lipid metabolism.
极低密度脂蛋白受体（VLDLR）是一种多功能载脂蛋白（apo）E受体，与低密度脂蛋白受体基因家族的成员具有共同的结构特征以及对apo E的一些配体特异性。我们已经分离并鉴定了小鼠VLDLR基因。小鼠VLDLR基因包含19个外显子，跨度约为50 kb。该基因的外显子-内含子组织在小鼠和人类之间完全保守。由于小鼠VLDLR基因的5'侧翼区域包含两个固醇调节元件-1样序列（SRE-1）拷贝，我们接下来研究了在喂食正常饲料或致动脉粥样化饮食的C57BL/6、LDLR-/-、apo E-/-和LDLR-/-apo E-/-小鼠的心脏、骨骼肌和脂肪组织中VLDLR mRNA表达的调节。仅在LDLR-/-小鼠中，喂食致动脉粥样化饮食会使心脏和骨骼肌中的VLDLR mRNA表达下调3倍。相比之下，在除双敲除小鼠外的所有动物模型中，致动脉粥样化饮食会使脂肪组织中的VLDLR mRNA表达上调。这些结果表明，SRE-1可能具有功能，并且当不存在LDLR时，VLDLR在心脏和骨骼肌的胆固醇稳态中起作用，并且这种调节需要apo E。VLDLR mRNA表达的发育调节也是组织特异性的。心脏中VLDLR mRNA表达在发育过程中表现出显著的上调和下调。在出生后第3天检测到最高水平。然而，骨骼肌中的VLDLR mRNA水平除了在出生后第7天略有下降外，保持相对恒定。在肾脏和大脑中，VLDLR mRNA也在出生后第3天达到峰值，但此后保持相对恒定。在肝脏中，VLDLR mRNA表达非常低；在妊娠第19天时几乎检测不到，此后进一步下降。在脂肪组织中，VLDLR mRNA水平在出生后第13天增加，在断奶期间再次下降，然后继续增加。这种发育模式以及脂肪组织中的饮食调节支持了VLDLR在该组织脂质积累中起作用的观点。尽管VLDLR在心脏、肌肉和脂肪组织中的主要作用可能是脂质代谢，但该受体在其他组织中的发育模式表明VLDLR具有与脂质代谢无关的功能。
