Variation in Niemann-Pick C1-like 1 gene as a determinant of apolipoprotein B-100 kinetics and response to statin therapy in centrally obese men.
OBJECTIVE
Niemann-Pick C1-like 1 protein (NPC1L1) plays a key role in lipoprotein metabolism. We examined the association of common genetic polymorphisms in NPC1L1 on apolipoprotein (apo) B-100 metabolism and the response to statin treatment in 37 men with central obesity.


METHODS
Very-low density lipoprotein (VLDL) and low-density lipoprotein (LDL)-apoB kinetics were determined using stable isotope method. NPC1L1 genotypes (1735G > C, 25432A > C and 27677T > C) were determined by allele-specific methods. These three polymorphisms are defined as haplotype, namely 1735C-25432A-27677T, and was designated as 'haplotype 2'.


RESULTS
Relative to non-2/2 haplotype (n = 23), subjects with the 2/2 haplotype (n = 14) had significantly increased plasma concentrations of total, LDL-cholesterol, and total apoB (P < 0.05). The fractional catabolic rate (FCR) of LDL-apoB was significantly lower in 2/2 subjects compared with non-2/2 subjects (P < 0.05), with an associated increase in LDL-apoB pool size in the former group. Sixteen subjects were then treated with 40 mg atorvastatin (6 weeks): 2/2 subjects (n = 8) had a significantly greater reduction in plasma concentrations of cholesterol and total apoB and in LDL-apoB pool size, as well as a greater increase in LDL-apoB FCR compared with non-2/2 subjects. There were no significant treatment-related between-haplotype differences in VLDL-apoB kinetics or in plasma concentrations of lathosterol and campesterol.


CONCLUSIONS
Our data demonstrate that NPC1L1 2/2 haplotype was associated with variation in LDL-apoB metabolism and its response to statin therapy in centrally obese men, by a mechanism that did not involve changes in VLDL-apoB kinetics, nor cholesterol synthesis or absorption.
Chan
Dick C
DC
Metabolic Research Centre, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
Watts
Gerald F
GF
Wang
Jian
J
Hegele
Robert A
RA
van Bockxmeer
Frank M
FM
Barrett
P Hugh R
PH
D000328:Adult; D019440:Anti-Obesity Agents / Q000627:therapeutic use; D053299:Apolipoprotein B-100 / Q000097:blood / Q000378:metabolism*; D000069059:Atorvastatin; D015243:Cholesterol, VLDL / Q000097:blood / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D014644:Genetic Variation / Q000502:physiology; D005838:Genotype; D006538:Heptanoic Acids / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007700:Kinetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D011758:Pyrroles / Q000627:therapeutic use; D016896:Treatment Outcome
D019440:Anti-Obesity Agents; D053299:Apolipoprotein B-100; D015243:Cholesterol, VLDL; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human; D011758:Pyrroles; D000069059:Atorvastatin