Abstract 13869: Statin Therapy Improves Fractional Catabolic Rate of LDL without Affecting Impaired VLDL and VLDL Remnant Catabolism in Homozygous FH Patient Due to PCSK9 Gene Mutation: Evidence from Kinetic Study with Stable Isotope
Background: Statin decreases plasma low-density lipoprotein (LDL) cholesterol through activation of sterol regulatory element binding protein 2 (SREBP2) and ensuing induction of LDL receptor. SREBP2 also induces proprotein subtilisin/kexin type 9 (PCSK9), which degenerates LDL receptor, thus PCSK9 may cancel a part of LDL-cholesterol lowering effect of statin. A gain-of function mutation of PCSK9 gene is known as a third cause of familial hypercholesterolemia (FH). However, little is known about the lipoprotein metabolism after statin therapy in patients with FH due to PCSK9 gene mutation. Therefore, we examined a kinetic study using stable isotope.
Methods and Results: We enrolled a homozygous FH patient with PCSK9 E32K mutation (female, 47yr. LDL-cholesterol=247mg/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 and 20mg daily of atorvastatin therapy. Tracer/tracee ratio of apolipoprotein B (apoB) was determined by GC-MS and fractional catabolic rate (FCR) were determined by multi-compartment modeling. The FCR of LDL apoB of homozygous FH with PCSK9 gene mutation (E32K) was lower than those of controls (0.232 vs. 0.455±0.114 pools/day) and normalized by 20mg daily of atorvastatin therapy (0.450 pools/day). Interestingly, the production rate of very-LDL (VLDL) (28.6 vs. 12.7±4.5%), the direct removal of VLDL (47.6 vs. 14.6±18.7%) and VLDL remnant (45.2 vs. 1.8±2.1%) in FH were greater than those in controls, which were not affected by atorvastatin therapy (27.9%, 50.0% and 50.0%, respectively).
Conclusion: Homozygous patient with PCSK9 gene mutation (E32K) showed impaired catabolism of LDL as well as VLDL and its remnant suggesting the existence of another metabolic pathway of remnant lipoproteins. Thus, inhibition of PCSK9 may be alternative method for further cholesterol lowering therapy over statin alone.
- © 2012 by American Heart Association, Inc.