Mechanisms of reversed cholesterol transport.

Reverse cholesterol transport may be defined as the movement of cholesterol from tissues, organs and cells to the liver (hepatocytes). Once cholesterol enters the hepatocyte it may be catabolized to bile acids, excreted into bile as free cholesterol, secreted back into the plasma compartment in lipoproteins or esterified and stored in the liver. A fraction of the bile acid and cholesterol excreted into bile is lost in the feces and accounts for the major loss of cholesterol and its metabolites from the body. If cholesterol was not added to the body then the mechanisms of reverse transport, bile acid and cholesterol excretion would deplete the body of sterols. Of course the body can absorb dietary cholesterol and synthesize cholesterol to keep overall cholesterol homeostasis. The mechanisms of reverse transport involve 1) the physico-chemical state of cholesterol and potential for movement within peripheral cells, tissues and deposits (e.g., atherosclerotic plaques); 2) the net transfer of free cholesterol from cell, tissues and deposits to acceptors (especially lipoproteins); 3) the physical state of the acceptors (e.g., the core and surface of lipoproteins and their capacity to accept cholesterol; 4) the LCAT reaction; 5) the transfer proteins; 6) the lipase (LPL and HTGL) reactions; and finally 7) the functional state of the LDL and chylomicron remnant receptors in the liver. The net transport of cholesterol from peripheral tissues, deposits and cells to the liver first depends on the rate of influx into the cells plus the rate of de novo cholesterol synthesis being less than the rate of removal. The rates of net removal will depend upon the sum of a variety of complex steps by which cholesterol can move down a gradient to enter acceptors than be transferred to other lipoproteins which are in turn ultimately taken up by the liver. A potentially important fraction of cholesterol leaving cells may be converted into cholesterol ester by LCAT then transferred to larger particles which can then be taken up by receptor medicated endocytosis in the liver. The HDL system must have its phospholipids replenished by both the synthesis of nascent HDL and by the formation of phospholipid-rich surface remnants during lipolysis of nascent triglyceride-rich lipoproteins which enter the HDL fraction. Finally, functionally active and vigorous receptor mechanisms are needed to remove cholesterol-containing particles into the liver.