Abnormal in vivo metabolism of apoB-containing lipoproteins in human apoE deficiency

Abstract

The present study was undertaken to elucidate the metabolic basis for the increased remnants and lipoprotein(a) [Lp(a)] and decreased LDL apolipoprotein B (apoB) levels in human apoE deficiency. A primed constant infusion of 13 C 6 -phenylalanine was administered to a homozygous apoE-deficient subject. apoB-100 and apoB-48 were isolated, and tracer enrichments were determined by gas chromatography-mass spectrometry, then kinetic parameters were calculated by multicompartmental modeling. In the apoE-deficient subject, fractional catabolic rates (FCRs) of apoB-100 in VLDL and intermediate density lipoprotein and apoB-48 in VLDL were 3 ؋ , 12 ؋ , and 12 ؋ slower than those of controls. On the other hand, the LDL apoB-100 FCR was increased by 2.6 ؋ . The production rate of VLDL apoB-100 was decreased by 45%. In the Lp(a) kinetic study, two types of Lp(a) were isolated from plasma with apoE deficiency: buoyant and normal Lp(a). 125 I-buoyant Lp(a) was catabolized at a slower rate in the patient. However, 125 Ibuoyant Lp(a) was catabolized at twice as fast as 131 I-normal Lp(a) in the control subjects.In summary, apoE deficiency results in: 1) a markedly impaired catabolism of VLDL/chylomicron and their remnants due to lack of direct removal and impaired lipolysis; 2) an increased rate of catabolism of LDL apoB-100, likely due to upregulation of LDL receptor activity; 3) reduced VLDL apoB production; and 4) a delayed catabolism of a portion of Lp(a). Apolipoprotein E (apoE) functions as the ligand for receptors, including LDL receptor-related protein (LRP), VLDL receptor, and LDL receptor (1, 2), and is thus important for the metabolism of apoB-containing lipoproteins. apoE is also considered to be important for the lipolysis of triglyceride (TG)-rich lipoproteins (3-6) and has been reported to facilitate VLDL production in animal models (7,8). apoE knockout mice have elevated VLDL and remnants and developed atherosclerosis on a chow diet (9). There have been several reported cases of humans with genetic apoE deficiency (10). All cases have type III hyperlipoproteinemia and some of the patients developed premature atherosclerosis in favor of the concept that apoE is crucial in human lipoprotein metabolism.Two kinetic studies in apoE-deficient subjects have been reported. Schaefer et al. (10) performed a radiotracer study and reported an impaired VLDL metabolism, in particular apoB-48, in a single apoE-deficient patient. However, multicompartmental modeling was not employed, thus only VLDL apoB-100 and apo-B48 were mathematically analyzed. Gabelli et al. (11) reported, in an LDL kinetic study using the same patient, that the rate of catabolism of LDL apoB was increased in the apoE-deficiency patient despite the relatively lower affinity of the LDL particles for the LDL receptor. However, an overall scheme of apoB-containing lipoprotein metabolism in humans with apoE deficiency has not been established. To establish the effect of apoE deficiency on apoB-containing lipoproteins, we performed an in vivo kinetic ...

Human Lecithin:Cholesterol Acyltransferase Deficiency

“…Ten of 17 volunteers participated in the radiotracer study (controls A). The remaining 7 took part in the stable isotope study (controls B; previously reported by Ikewaki et al 14 ).…”

“…The detailed protocol for sample processing has been previously reported. 14,16 In brief, after a 12-hour fast, 13 C 6 -phenylalanine (99% 13 C 6 ; Cambridge Isotope Laboratories, Woburn, Mass) was administered to the study subject as a priming bolus of 600 g/kg, immediately followed by a constant infusion of 12 g/kg per minute for up to 12 hours. Blood samples (20 mL) were obtained at 10 minutes, 1, 2, 3, 4, 5, 6, and every 2 hours until the end of infusion, and then at 18, 24, 36, 48, and 72 hours.…”

Rapid turnover of apolipoprotein C-III-containing triglyceride-rich lipoproteins contributing to the formation of LDL subfractions

“…Overexpression of apoE in mice corrects the hypertriglyceridemia produced by the overexpression of apoC-III (16). Humans who are deficient in apoE, or who are homozygous for a defective isoform of apoE, have retarded metabolism of TRL and abnormal TRL composition (26,27). Thus, apoC-III and apoE may be viewed functionally as antagonists in apoB lipoprotein metabolism.…”

Apolipoprotein Isoform E4 Does Not Increase Coronary Heart Disease Risk in Carriers of Low-Density Lipoprotein Receptor Mutations

“…4,5 Homozygous deficiency of the APOE gene in humans is extremely rare and is also characterized by atherogenic lipid abnormalities and premature CHD. 6,7 Clinical Perspective on p 660…”

“…4,5 Homozygous deficiency of the APOE gene in humans is extremely rare and is also characterized by atherogenic lipid abnormalities and premature CHD. 6,7 Clinical Perspective on p 660In humans, 3 main haplotypes of the APOE gene have been identified: APOE2, APOE3, and APOE4. The encoded ApoE2, ApoE3, and ApoE4 proteins differ in their amino acid sequences at positions 112 and 158.…”