Cholesterol suppresses cellular TGF-β responsiveness: Implications in atherogenesis

Chun Lin Chen, I. Hua Liu, Steven J. Fliesler, Xianlin Han, Shuan Shian Huang, Jung San Huang

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

Hypercholesterolemia is a major causative factor for atherosclerotic cardiovascular disease. The molecular mechanisms by which cholesterol initiates and facilitates the process of atherosclerosis are not well understood. Here, we demonstrate that cholesterol treatment suppresses or attenuates TGF-β responsiveness in all cell types studied as determined by measuring TGF-β-induced Smad2 phosphorylation and nuclear translocation, TGF-β-induced PAI-1 expression, TGF-β-induced luciferase reporter gene expression and TGF-β-induced growth inhibition. Cholesterol, alone or complexed in lipoproteins (LDL, VLDL), suppresses TGF-β responsiveness by increasing lipid raft and/or caveolae accumulation of TGF-β receptors and facilitating rapid degradation of TGF-β and thus suppressing TGF-β-induced signaling. Conversely, cholesterol-lowering agents (fluvastatin and lovastatin) and cholesterol-depleting agents (β-cyclodextrin and nystatin) enhance TGF-β responsiveness by increasing non-lipid raft microdomain accumulation of TGF-β receptors and facilitating TGF-β-induced signaling. Furthermore, the effects of cholesterol on the cultured cells are also found in the aortic endothelium of ApoE-null mice fed a high-cholesterol diet. These results suggest that high cholesterol contributes to atherogenesis, at least in part, by suppressing TGF-β responsiveness in vascular cells.

Original languageEnglish (US)
Pages (from-to)3509-3521
Number of pages13
JournalJournal of cell science
Volume120
Issue number20
DOIs
StatePublished - Oct 15 2007

Keywords

  • Cholesterol
  • TGF-β
  • TGF-β receptors

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'Cholesterol suppresses cellular TGF-β responsiveness: Implications in atherogenesis'. Together they form a unique fingerprint.

Cite this