Department of Biological Chemistry at UCLA Los Angeles, CA 90095, USA.
J Lipid Res. 2010 Jan;51(1):169-81. doi: 10.1194/M900250-JLR200.
ABCG1 and ABCG4 are highly homologous members of the ATP binding cassette (ABC) transporter family that regulate cellular cholesterol homeostasis. In adult mice, ABCG1 is known to be expressed in numerous cell types and tissues, whereas ABCG4 expression is limited to the central nervous system (CNS). Here, we show significant differences in expression of these two transporters during development. Examination of beta-galactosidase-stained tissue sections from Abcg1(-/-)LacZ and Abcg4(-/-)LacZ knockin mice shows that ABCG4 is highly but transiently expressed both in hematopoietic cells and in enterocytes during development. In contrast, ABCG1 is expressed in macrophages and in endothelial cells of both embryonic and adult liver. We also show that ABCG1 and ABCG4 are both expressed as early as E12.5 in the embryonic eye and developing CNS. Loss of both ABCG1 and ABCG4 results in accumulation in the retina and/or brain of oxysterols, in altered expression of liver X receptor and sterol-regulatory element binding protein-2 target genes, and in a stress response gene. Finally, behavioral tests show that Abcg4(-/-) mice have a general deficit in associative fear memory. Together, these data indicate that loss of ABCG1 and/or ABCG4 from the CNS results in changes in metabolic pathways and in behavior.
ABCG1 和 ABCG4 是高度同源的 ATP 结合盒（ABC）转运体家族成员，它们调节细胞内胆固醇稳态。在成年小鼠中，已知 ABCG1 在多种细胞类型和组织中表达，而 ABCG4 的表达仅限于中枢神经系统（CNS）。在这里，我们在发育过程中观察到这两种转运体表达的显著差异。对 Abcg1(-/-)LacZ 和 Abcg4(-/-)LacZ 敲入小鼠的β-半乳糖苷酶染色组织切片进行检查，结果表明 ABCG4 在发育过程中在造血细胞和肠细胞中高度但短暂表达。相比之下，ABCG1 在胚胎和成年肝脏的巨噬细胞和内皮细胞中表达。我们还表明，ABCG1 和 ABCG4 早在胚胎眼和发育中的中枢神经系统的 E12.5 就表达了。ABCG1 和 ABCG4 的缺失会导致氧化固醇在视网膜和/或大脑中积累，改变肝脏 X 受体和固醇调节元件结合蛋白-2 靶基因的表达，并导致应激反应基因的表达。最后，行为测试表明 Abcg4(-/-) 小鼠在联想性恐惧记忆方面存在普遍缺陷。综上所述，这些数据表明，中枢神经系统中 ABCG1 和/或 ABCG4 的缺失会导致代谢途径和行为发生变化。
