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Inhibition of cholesterol biosynthesis disrupts lipid raft/caveolae and affects insulin receptor activation in 3T3-L1 preadipocytes.
- Source :
-
Biochimica et biophysica acta [Biochim Biophys Acta] 2009 Sep; Vol. 1788 (9), pp. 1731-9. Date of Electronic Publication: 2009 May 09. - Publication Year :
- 2009
-
Abstract
- Lipid rafts are plasma membrane microdomains that are highly enriched with cholesterol and sphingolipids and in which various receptors and other proteins involved in signal transduction reside. In the present work, we analyzed the effect of cholesterol biosynthesis inhibition on lipid raft/caveolae composition and functionality and assessed whether sterol precursors of cholesterol could substitute for cholesterol in lipid rafts/caveolae. 3T3-L1 preadipocytes were treated with distal inhibitors of cholesterol biosynthesis or vehicle (control) and then membrane rafts were isolated by sucrose density gradient centrifugation. Inhibition of cholesterol biosynthesis with either SKF 104976, AY 9944, 5,22-cholestadien-3beta-ol or triparanol, which inhibit different enzymes on the pathway, led to a marked reduction in cholesterol content and accumulation of different sterol intermediates in both lipid rafts and non-raft domains. These changes in sterol composition were accompanied by disruption of lipid rafts, with redistribution of caveolin-1 and Fyn, impairment of insulin-Akt signaling and the inhibition of insulin-stimulated glucose transport. Cholesterol repletion abrogated the effects of cholesterol biosynthesis inhibitors, reflecting they were specific. Our results show that cholesterol is required for functional raft-dependent insulin signaling.
- Subjects :
- 3T3-L1 Cells
Animals
Caveolae metabolism
Caveolin 1 metabolism
Dehydrocholesterols pharmacology
Enzyme Inhibitors pharmacology
G(M1) Ganglioside metabolism
Lanosterol analogs & derivatives
Lanosterol pharmacology
Mice
Receptor, Insulin drug effects
Receptor, Insulin metabolism
Triparanol pharmacology
trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride pharmacology
Caveolae drug effects
Cell Membrane metabolism
Cholesterol biosynthesis
Membrane Microdomains drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0006-3002
- Volume :
- 1788
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta
- Publication Type :
- Academic Journal
- Accession number :
- 19433058
- Full Text :
- https://doi.org/10.1016/j.bbamem.2009.05.002