Reverse cholesterol transport (high-density lipoprotein pathway)
The removal of cholesterol from tissues back to the liver via HDLs represents the only route of elimina-tion for cholesterol from the body. This physiological role of HDLs explains, in part, the cardioprotective effects of these lipoproteins, as indicated by a strong inverse relationship between serum HDL cholesterol and CHD risk in prospective cohort studies.
Figure 6.9 Reverse cholesterol trans-port. CE, cholesterol ester; CETP, choles-terol ester transfer protein; HDL, high-density lipoprotein; LCAT, lecithin– cholesterol acyltransferase; LDL, low-density lipoprotein; LPL, lipoprotein lipase; VLDL, very low-density lipoprotein.
The activity of the HDL pathway is influenced by genetic and dietary factors that can interact to either increase or reduce the efficiency of cholesterol removal. This, in turn, may be reflected in changes in the concentra-tion of serum HDLs and their functional properties.
HDLs are synthesized in the gut and liver, and increase their particle size in the circulation as a result of the acquisition of cholesterol from two principal sources: (1) surface material released from TAG-rich lipoproteins during lipolysis and (2) peripheral tissues. The particles, which are responsible for removing cholesterol from cells, are very small pre-HDLs and are disk-shaped particles composed of phospholipid and apoA-I (ApoA-I is capable of this function on its own). The efflux of free cholesterol from tissue sites, including deposits of cholesterol in the coronary arteries, is facilitated by the formation of a free cholesterol gradient from the cell across the cell membrane to pre-HDLs. The gradient is gener-ated by the re-esterification of free cholesterol by the enzyme lecithin–cholesterol acyltransferase (LCAT) and via the migration of these newly formed choles-terol esters into the hydrophobic core of what becomes mature, spherical HDL. The newly acquired choles-terol is transported back to the liver either directly by HDL or indirectly by transfer to apoB-containing lipoproteins VLDL and LDL. Blood vessels in the liver contain a close relative of LPL, i.e., HL. This enzyme acts on smaller lipoproteins and especially the surface phospholipid of HDL, where it effectively punches a hole in the surface coat to facilitate access to the lipid core and delivery of CE to the hepatocyte (Figure 6.9).
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