The process of high-density lipoprotein (HDL) maturation is important for reverse cholesterol transport, a hypothesis that HDL transports cholesteryl ester (CE) from peripheral atherosclerotic lesions to the liver. This hypothesis is based on epidemiological studies that indicated an inverse correlation between the HDL cholesterol (HDL-C) levels and the prevalence of coronary heart disease (CHD) as an independent anti-atherogenic factor for CHD. It is therefore interesting to note that despite a markedly low level of HDL-C and a loss of the HDL maturation process, CHD is not a common complication in patients lacking lecithin:cholesterol acyltransferase (LCAT).? ? LCAT is an enzyme that esterifies free cholesterol (FC) into cholesteryl ester (CE) in HDL. Human LCAT deficiency (LCAT-def) is characterized by corneal opacity, anemia, and proteinuria, with low levels of HDL and low density lipoprotein (LDL) and the accumulation of lipoprotein-X (LpX). LpX is a unique lipoprotein characterized by a balloon-like structure constructed of phospholipid, FC, apolipoprotein A-I, and albumin. HDL is markedly decreased, together with abnormalities in size and lipid composition in LCAT-def. Most of the HDL in LCAT-def is small and discoidal, a characteristic resembling newly synthesized HDL. In the absence of LCAT, newly synthesized HDL cannot esterify FC to CE in its core so that HDL cannot develop into its mature stable forms of either HDL2 or HDL3. ? ? Our aim was to elucidate the mechanism(s) responsible for the decreased LDL level and to determine the plasma kinetics of LpX in LCAT-def. We conducted radiotracer and stable isotope studies in LCAT-def patients and control subjects, which allowed us to analyze the conversion from VLDL to LDL by endogenously labeling VLDL apoB-100. The LDL fraction was separated by ultracentrifugation then the plasma was injected into FPLC and LDL was subsequently separated from LpX at each time point. No conversion was observed between the two particles. This combined approach permitted us to investigate the mechanism underlying the low levels of LDL in LCAT-def and provided new insight into the low risk of premature CHD in this disorder despite a markedly decreased HDL-C.? ? LCAT-def LDL was catabolized faster than control LDL in the control subjects as well as in LCAT-def patients. Control LDL was catabolized faster in LCAT-def patients than the controls. Despite this, the production rate of LDL apolipoprotein B-100 was normal in LCAT-def. The decreased LDL in LCAT-def was attributable to an increased catabolism caused by a rapid catabolism of abnormal LDL and an upregulation of the LDL receptor pathway. Two separate mechanisms are considered to contribute to the rapid catabolism of LDL: namely, a rapid catabolism of abnormal LDL and an upregulation of LDL-R pathway. In addition, the catabolism of LpX was decreased in LCAT-def and this contributed to the LpX accumulation in this disorder. The profound changes in the metabolism of apoB-containing lipoproteins in LCAT def provided a mechanistic basis for there lowered atherogenic potential.
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