Lessons from molecular defects in secretion, transport and reverse transport of cholesterol

Genetic defects of cholesterol secretion, transport, reverse transport and recycling pathways produce dyslipidemias. Abetalipoproteinemia due to microsomal triglyceride transfer protein (MTP) deficiency produces severe hypolipidemia, and it is proposed that inhibition of MTP will provide a specific mechanism for lowering plasma cholesterol and triglyceride levels. The data of death in familial hypercholesterolemia (FH) showed a curve of incidence of coronary heart disease (CHD) in each cholesterol level, and this line separates benefit and no benefit areas by cholesterol-lowering therapy. Lecithin cholesterol acyltransferase (LCAT) deficiency produces a complete obstruction of the reverse cholesterol transport, but LCAT deficiency does not necessarily produce atherosclerosis, probably due to concomitant low level of LDL-cholesterol. An interruption of cholesterol recycling pathway by blocking cholesteryl ester transfer protein (CETP) activity will produce antiatherogenic lipoprotein profile observed in CETP deficiency. As a conclusion for the treatment of hypercholesterolemia, all the "physiological" pathways supplying cholesterol to low-density lipoprotein (LDL) should be blocked.