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Cholesterol Suppresses Cellular TGF‐beta Responsiveness by Increasing TGF‐beta Receptor Accumulation in Lipid raft/Caveolae Microdomains and Alterring TGF‐beta Binding to TGF‐beta Receptors
Author(s) -
Chen ChunLin,
Huang Shuan Shian,
Huang Jung San
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.645.7
Subject(s) - caveolae , lipid raft , cholesterol , receptor , transforming growth factor beta , endocytosis , tgf beta signaling pathway , endocrinology , transforming growth factor , medicine , microbiology and biotechnology , ldl receptor , biology , chemistry , signal transduction , lipoprotein
TGF‐β responsiveness in cultured cells can be modulated by TGF‐β partitioning between lipid raft/caveolae‐ and clathrin‐mediated endocytosis pathways. The ratio of TGF‐β binding to TβR‐II and TβR‐I on the cell surface has recently been found to be a signal that controls TGF‐β partitioning between these pathways. Since cholesterol is a structural component in lipid rafts/caveolae, we have studied the effects of cholesterol on TGF‐β binding to TGF‐β receptors and TGF‐β responsiveness in cultured cells and in animals. Here we demonstrate that treatment with cholesterol decreases the TβR‐II/TβR‐I binding ratio of TGF‐β while treatment with cholesterol‐lowering or cholesterol‐depleting agents increases the TβR‐II/TβR‐I binding ratio of TGF‐β in all cell types studied. Cholesterol treatment increases accumulation of the TGF‐β receptors in lipid rafts/caveolae microdomains of the plasma membrane. Cholesterol/LDL suppresses TGF‐β responsiveness and statins/β‐CD enhances it, as measured by the levels of P‐Smad2 and PAI‐1 expression. Furthermore, the cholesterol effects observed in cultured cells are also found in the aortic endothelium of atherosclerotic ApoE‐null mice fed a high cholesterol diet. These results indicate that high plasma cholesterol levels contribute to the pathogenesis of atherosclerosis, at least in part, by suppressing TGF‐β responsiveness.