Chaperone Complexes Involved in Cholesterol Transport in Specialized Tissues

The intestine has a major role in the overall regulation of systemic cholesterol levels. We have identified a third chaperone complex that is involved in the net uptake and transport of cholesterol in the intestine [80]. Annexin II and caveolin-1 form a chaperone complex with cyp40 and cypA that binds cholesterol in the intestine. Ablation of annexin II or caveolin-1 in the zebrafish disrupted cholesterol uptake. Further, the drug ezetimibe decreased cholesterol levels in the circulation by disrupting intestinal cholesterol transport. Ezetimibe also disrupted this novel annexin II-caveolin-cholesterol chaperone complex. However, the interaction of annexin II with caveolin-1 in this intestinal complex is quite different from the two chaperone complexes described previously. Annexin II and caveolin-1 appear to form a heterodimeric band which is stable to heat, SDS and reducing agents, and was also immunoreactive against both annexin II and caveolin-1 and resolved as a complex at 55-58 kDa on SDS gels. This band, after digestion and analysis, yielded several peptides corresponding to regions of each individual protein, and its size was consistent with that of a heterodimeric complex. This novel complex is not limited to zebrafish, however. In mouse intestine, a band that corresponds to this heterodimeric complex, along with immunoreactive bands corresponding to the monomeric forms of each protein were also found. Recently, another protein -NPC1 like 1 protein, has been found in intestine, and shown to regulate intestinal cholesterol and sitosterol uptake [81,82]. NPC-1 fibroblasts (which lack functional NPC-1, the first protein in this family) show a block in cholesterol transport causing accumulation of cholesterol-rich late endosomes [83]. In these cells, both caveolin and annexin II exhibit elevated expression and accumulation with cholesterol in late endosomes. Further studies will be needed to determine the relationship between these two overlapping pathways and their roles in intestinal cholesterol trafficking.

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