Abstract 8252: Altered Metabolism of Post-Prandial Remnant Lipoprotein Fractions in Autosomal Recessive Hypercholesterolemia

Abstract

Introduction: Autosomal recessive hypercholesterolemia (ARH) associated with mutations in LDLR adaptor protein 1 (LDLRAP1) gene is extremely rare disorder. Although this defect seems to be a phenocopy of homozygous familial hypercholesterolemia (FH), clinical phenotype of ARH seems less severe, more responsive to statins, the cause of which may be derived from the difference of remnant-like particles (RLP) clearance. Hypothesis: We assessed the hypothesis that the ability of RLP clearance of ARH subject was different from that of FH subject. Methods: OFTT cream (Jomo Shokuhin, Takasaki, Japan) 50 g was given per body surface area (squared meter), blood sampling was performed at 2 hour intervals up to 6 hour. Plasma lipoprotein and RLP fraction were determined by HPLC system in one ARH subject (68yr, LDL-C=286mg/dl), 4 heterozygous FH subjects (58±17yr, LDL-C=241±26mg/dl), and 4 controls (62±17yr, LDL-C=88±6mg/dl). All male subjects were selected to have apolipoprotein E2/E3 phenotype without diabetes. None of the subjects took medication known to affect plasma lipids at the time of this study for at least 4 weeks. The area under curve (AUC) of TG, RLP-TG, and RLP-cholesterol levels were evaluated. Results: After oral fat load, the AUC of TG, RLP-TG, and RLP-cholesterol levels of heterozygous FH subjects were significantly increased compared to those of controls (441±87 mg/dl*hour vs 316±133 mg/dl*hour, p<0.05, 126±60 mg/dl*hour vs 49±11 mg/dl*hour, p<0.05, 34±8 mg/dl*hour vs 23±11 mg/dl*hour, p<0.05, respectively). In contrast to these results, the AUC of TG, RLP-TG, and RLP-cholesterol levels of ARH were within the nomal range (310mg/dl*hour, 23mg/dl*hour, 22mg/dl*hour, respectively). Conclusions: These results suggest that the lack of LDLRAP1 modulates RLP metabolism, activating an alternate pathway which can remove remnant fraction paradoxically. This preferred pathway should contribute to the greater responsiveness to statins. Our results will provide new insights into the lipoprotein metabolism of ARH and the novel pharmacological target for LDLRAP1.