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1 Urology, Albert Einstein College of Medicine, Bronx, New York, United States; Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, United States
2 Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, United States
* To whom correspondence should be addressed. E-mail: pfrank{at}aecom.yu.edu.
Caveolae are 50-100 nm cell surface plasma membrane invaginations present in terminally differentiated cells. Caveolin-1 is thought to play an important role in the regulation of cellular cholesterol homeostasis, a process that needs to be properly controlled in order to limit and prevent cholesterol accumulation and eventually atherosclerosis. 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 when compared to their wild-type counterparts. Similarly, Cav-1(-/-) MPMs also contained less free cholesterol and were enriched in esterified cholesterol, upon 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 up regulated upon cholesterol loading. Despite these differences, cellular cholesterol efflux from MEFs and MPMs to HDL was not affected in the Cav-1-deficient cells. Cellular cholesterol efflux to apolipoprotein A-I was not significantly reduced in Cav-1(-/-) MPMs, as compared to 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.
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