Two Chaperone Complexes Regulate a Caveola Cholesterol Trafficking Cycle

In addition to organizing cholesterol in caveolae, caveolin has been found to play a specific role in nonvesicular cholesterol trafficking in cells. A direct role for cav-eolin in trafficking newly synthesized cholesterol from the ER to the plasma membrane was shown in cells which lacked caveolin and in which caveolin was re-expressed. Radiolabeled tracers and blockers of cholesterol transport were used to show that caveolin and cholesterol trafficked together from intracellular sites to cell-surface caveolae [49]. A subsequent study revealed that a chaperone complex ferries newly synthesized cholesterol from the ER through the cytosol to plasma membrane caveolae [50]. This chaperone complex was isolated from the cytosol, distinct from any caveola membrane, plasma membrane, intracellular membrane or vesicle fraction. The complex was shown to be comprised of cholesterol, cav-eolin-1 and three additional proteins - cyclophilin A (cypA), cyclophilin 40 (cyp40), and heat shock protein 56 (hsp56). The activity of this complex could be inhibited by compounds which bind to and inhibit the function of hsp56 (rapamycin) or interact with cyclophilins (cyclosporine). Either of these inhibitors prevented the formation of the chaperone complex and blocked cholesterol movement from the Golgi to plasma membrane caveolae.

The linkage between caveolin movement in and out of caveolae to caveolae cholesterol homeostasis led to the subsequent identification of a second chaperone complex which regulates transport of newly delivered cholesterol into the cell. This second complex consists of cholesteryl ester, caveolin-1, cypA, cyp40, and annexin II [10]. HDL can deliver cholesteryl ester to caveolae via scavenger receptor BI (SR-BI). Cholesteryl ester is then transported via this complex into the cell, where it can be converted to cholesterol and transported back to the cell surface to caveolae via the first chaperone complex. These two complexes provide a nonvesicle pathway which can regulate cholesterol uptake and delivery from caveolae in fibroblasts and other caveolin-1-containing cells, but not in cells such as hepatocytes, which normally contain minimal caveolin-1.

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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