Abstract 1314: Impact of Increased Catabolism of VLDL Remnant in Autosomal Recessive Hypercholesterolemia: A Stable Isotope Kinetic Study in vivo
Autosomal recessive hypercholesterolemia (ARH), which is due to mutations in an adaptor protein involved in LDLR internalization (LDLRAP1) is extremely rare disorder, and is described only about 50 cases in the world. This defect seems to be a phenocopy of homozygous FH, however, clinical phenotype of ARH seems less severe, more responsive to statins, the mechanism of which still remains unknown. We identified the second Japanese ARH family (InsC599, male, 68 yr, LDL-C=246mg/dl). An ARH patient and 8 controls (male=7, 41±8 yr, LDL-C=119±19mg/dl) were given a bolus injection (10mg/kg) of [2H3]-leucine (Cambridge Isotope Laboratories, Woburn, MA). Blood samples were drawn periodically for 48 hours. These studies were performed at baseline and after the 20mg daily of atorvastatin. Tracer/tracee ratio of apoB was determined by gas chromatography/mass spectrometry and fractional catabolic rates (FCR) were determined by multi-compartmental modeling (SAAMII, version 1.1; SAAM Institute Inc). As expected, FCR of LDL apoB of ARH patient was significantly lower than those of normal controls (0.306 pools/day vs 0.455±0.114 pools/day). Surprisingly and strikingly contrast to FH, FCR of LDL apoB of ARH patient was almost normalized after atorvastatin therapy (0.464 pools/day). In addition, the removals of VLDL remnant (40% vs 2±2%) was significantly greater compared with normal controls. This tendency became much more pronounced after atorvastatin therapy. Using stable isotope methodology, we showed thatthe lack of LDLRAP1 modulates VLDL metabolism, activating a alternate pathway which can remove VLDL remnant 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.