Abstract 14785: Impact of Impaired LDL Catabolism and Increased VLDL and VLDL Remnant Production on Hypercholesterolemia in Homozygous PCSK9 Gene Mutation: Evidence from Kinetic Study with Stable Isotope
Background: Statin activates sterol regulatory element binding protein 2 (SREBP2) due to depletion of cholesterol in hepatocyte and results both in induction of low-density lipoprotein (LDL) receptor and proprotein convertase subtilisin/kexin type 9 (PCSK9) gene. PCSK9 is known to increase the degradation of LDL receptor, thus it may cancel a part of LDL-cholesterol lowering effect of statin. Moreover, PCSK9 is recognized as a third cause of familial hypercholesterolemia (FH). Although we identified 2 true homozygous FH patients with PCSK9 gene mutation (E32K), few data exist regarding the detailed metabolism of homozygous FH due to PCSK9 gene mutation compared with normal controls. Therefore, we examined lipoprotein metabolism in homozygous FH patients with PCSK9 gene mutation (E32K) using stable isotope method.
Methods and Results: We enrolled 2 homozygous FH patients with PCSK9 E32K mutation (female=2, 53±9yr., LDL-C=286±42mg/dL) and 8 control subjects (female=1, 41±8yr., LDL-C=119±19mg/dL) who were given 10mg/kg of [2H3]-leucine after wash-out of any lipid lowering drugs. Tracer/tracee ratio of apolipoprotein B (apoB) was determined by GC-MS and fractional catabolic rate (FCR) were determined by multi-compartment modeling. As expected, FCR of LDL apoB of homozygous FH with PCSK9 gene mutation (E32K) was significantly lower than those of controls (0.217±0.021 vs. 0.455±0.114 pools/day). Interestingly, the production rate of very-LDL (VLDL)(29.6±1.5 vs. 12.7±4.5), the direct removal of VLDL (42±6 vs. 15±19%) and VLDL remnant (41±5 vs. 2±2%) were significantly greater compared with those of controls, suggesting the existence of another metabolic pathway of VLDL remnant.
Conclusion: Homozygous patients with PCSK9 gene mutation (E32K) showed impaired catabolism of LDL as well as VLDL. Thus, inhibition of PCSK9 may be alternative method for further cholesterol lowering therapy over statin alone.
- © 2011 by American Heart Association, Inc.