The investigation of familial hypercholesterolemia (FH) and its relationship to atherosclerosis has led to enormous scientific and medical progress, including the identification of genetic defects underlying FH, the elucidation of molecular mechanisms crucial for cellular cholesterol homeostasis and the development of current pharmaceutical tools for FH treatment (which are directed at increasing LDL uptake). These successes also led to the establishment of a model centered on cellular rather than whole organism processes, and a view of FH as resulting from a deficiency in LDL uptake. On the other hand, whole organism fluxes of cholesterol (like those of other nutrients) are centered on the liver, LDL (ultimately derived from the liver) is the main cholesterol transporter in plasma, and there is evidence of evolutionary pressure favoring mechanisms to maintain LDL plasma concentrations. Furthermore, the alterations in cellular metabolism observed in FH are consistent with a coordinated response by the liver to increase the levels of plasma LDL, suggesting that a signaling defect (rather than an uptake deficiency) is the fundamental problem underlying hypercholesterolemia – an hypothesis that explains the occurrence of hypercholesterolemia in CESD, despite normal LDL binding and uptake. I therefore propose that the liver contains a mechanism to assess and regulate plasma levels of LDL (an “LDL-ostat”), and that hypercholesterolemia is caused by defects in it. This model has implications for future research directions, and suggests alternative therapeutic approaches, particularly centered on efforts to restore LDL measurement/signaling (rather than its uptake), some of which are in stark contrast to those currently in use.

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PubMed