title: Caveolin-1 and regulation of cellular cholesterol homeostasis.
abstract: 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.
authors.affiliation: Department of Urology, and Albert Einstein Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York, USA. Philippe.Frank@jefferson.edu
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Frank
authors.forename: Michelle W-C
authors.initials: MW
authors.lastname: Cheung
authors.forename: Stephanos
authors.initials: S
authors.lastname: Pavlides
authors.forename: Gemma
authors.initials: G
authors.lastname: Llaverias
authors.forename: David S
authors.initials: DS
authors.lastname: Park
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D000818:Animals; D001054:Apolipoproteins A / Q000378:metabolism; D015153:Blotting, Western; D051242:Caveolin 1 / Q000235:genetics / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D066298:In Vitro Techniques; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
chemical_list: D001054:Apolipoproteins A; D051242:Caveolin 1; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D051780:Sterol Regulatory Element Binding Protein 1; D002784:Cholesterol