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Fig. 10. A model for the cholesterol effect on TGF- partitioning between lipid rafts/caveolae- and clathrin-mediated endocytosis. In cells, there are two major TR-I–TR-II complexes (Complex I and Complex II) present on the cell face. Complex I and Complex II are mainly localized in the non-lipid raft and lipid raft/caveolae microdomains of the plasma membrane, respectively. The numbers of TR-I and TR-II molecules (blue rectangles) in Complex I and Complex II shown in the model are arbitrary and intended to indicate that Complex I and Complex II contain TR-II>TR-I and TR-I>TR-II, respectively. The ratio of TR-II to TR-I can be determined by ¹²⁵I-TGF-1 affinity labeling (Chen et al., 2006). Cholesterol increases the formation and/or stabilization of lipid rafts/caveolae by integration into the plasma membrane, thereby increasing the localization of TR-I and TR-II in lipid rafts/caveolae (as Complex II), facilitating rapid degradation of TGF- and attenuating TGF- responsiveness (Smad dependent). Complex II may also be capable of mediating Smad2/3-indepentent signaling which leads to different cellular responsiveness such as fibrogenesis in fibroblasts (Pannu et al., 2007). Depletion of cholesterol in the plasma membrane, by treating cells with cholesterol-lowering agents (e.g. statins) or cholesterol-depleting agents (e.g. -CD), facilitates the localization of TR-I and TR-II in non-lipid raft microdomains. In the presence of ligand, Complex I undergoes clathrin-mediated endocytosis, promoting Smad2/3-dependent endosomal signaling and TGF- responsiveness. In hypercholesterolemic mice, cell-surface TGF- receptor complexes in the aortic endothelium contain more Complex II than Complex I. In normal mice, cell-surface TGF- receptor complexes contain more Complex I than Complex II in the aortic endothelium.

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