Caveolin-1 and regulation of cellular cholesterol homeostasis
Caveolin-1 and regulation of cellular cholesterol homeostasis
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DOI：
10.1152/ajpheart.01092.2005
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发表时间：
2006-08-01
影响因子：
4.8
通讯作者：
Lisanti, Michael P.
中科院分区：
文献类型：
--
作者：
Frank, Philippe G.;Cheung, Michelle W. -C.;Lisanti, Michael P.
小凹是终末分化细胞中存在的 50 至 100 nm 细胞表面质膜内陷。它们的特征是含有 Caveolin-1、鞘脂和胆固醇。 Caveolin-1被认为在细胞胆固醇稳态的调节中发挥着重要作用，这一过程需要适当控制以限制和防止胆固醇积累并最终导致动脉粥样硬化。我们最近培育了caveolin-1缺陷型[Cav-1(-/-)]小鼠，其中除心肌和骨骼肌外，所有细胞类型中的caveolae细胞器均被完全消除。在本研究中，我们检测了野生型（WT）和Cav-1（-/-）小鼠胚胎成纤维细胞（MEF）和小鼠腹膜巨噬细胞（MPM）中胆固醇的代谢。我们观察到，与野生型对应物相比，Cav-1(-/-) MEF 富含酯化胆固醇，但不含游离胆固醇。类似地，Cav-1(-/-) MPM 也含有较少的游离胆固醇，并且在胆固醇负载上富含酯化胆固醇。与这一发现一致，caveolin-1 缺乏与游离胆固醇合成减少有关，但与酰基辅酶 A：胆固醇酰基转移酶 (ACAT) 活性增加有关。在野生型 MPM 中，我们观察到 Caveolin-1 在胆固醇负荷上显着上调。尽管存在这些差异，但在 Cav-1 缺陷细胞中，从 MEF 和 MPM 到 HDL 的细胞胆固醇流出并未受到影响。 ATP 结合盒转运蛋白 G1 (ABCG1) 和 B 型清道夫受体 I 型 (SR-BI) 介导的胆固醇流出均不受影响。与野生型 MPM 相比，Cav-1(-/-) MPM 中细胞胆固醇流出至载脂蛋白 A-I 并未显着减少。然而，与 WT MPM 相比，ABCA1 介导的胆固醇流出显然对 Cav-1(-/-) MPM 中格列本脲的抑制作用更敏感。总而言之，这些发现表明，caveolin-1 在细胞内胆固醇稳态的调节中发挥着重要作用，并且可以调节参与细胞内胆固醇稳态调节的其他蛋白质的活性。
Caveolae are 50- to 100-nm cell surface plasma membrane invaginations present in terminally differentiated cells. They are characterized by the presence of caveolin-1, sphingolipids, and cholesterol. Caveolin-1 is thought to play an important role in the regulation of cellular cholesterol homeostasis, a process that needs to be properly controlled to limit and prevent cholesterol accumulation and eventually atherosclerosis. We have recently generated caveolin-1-deficient [Cav-1(-/-)] mice in which caveolae organelles are completely eliminated from all cell types, except cardiac and skeletal muscle. In the present study, we examined the metabolism of cholesterol in wild-type (WT) and Cav-1(-/-) mouse embryonic fibroblasts (MEFs) and mouse peritoneal macrophages (MPMs). We observed that Cav-1(-/-) MEFs are enriched in esterified cholesterol but depleted of free cholesterol compared with their wild-type counterparts. Similarly, Cav-1(-/-) MPMs also contained less free cholesterol and were enriched in esterified cholesterol on cholesterol loading. In agreement with this finding, caveolin-1 deficiency was associated with reduced free cholesterol synthesis but increased acyl-CoA: cholesterol acyl-transferase (ACAT) activity. In wild-type MPMs, we observed that caveolin-1 was markedly upregulated on cholesterol loading. Despite these differences, cellular cholesterol efflux from MEFs and MPMs to HDL was not affected in the Cav-1-deficient cells. Neither ATP-binding cassette transporter G1 (ABCG1)-nor scavenger receptor class B type I (SR-BI)-mediated cholesterol efflux was affected. Cellular cholesterol efflux to apolipoprotein A-I was not significantly reduced in Cav-1(-/-) MPMs compared with wild- type MPMs. However, ABCA1-mediated cholesterol efflux was clearly more sensitive to the inhibitory effects of glyburide in Cav-1(-/-) MPMs versus WT MPMs. Taken together, these findings suggest that caveolin-1 plays an important role in the regulation of intracellular cholesterol homeostasis and can modulate the activity of other proteins that are involved in the regulation of intracellular cholesterol homeostasis.