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.

Abstract

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.

RESEARCH METHODS AND PROCEDURE:

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.

CONCLUSION:

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.

• Authors: Dick C Chan, Gerald F Watts, Jian Wang, Robert A Hegele, Frank M van Bockxmeer, P Hugh R Barrett
• Journal: Clinical endocrinology (Clin Endocrinol (Oxf)) Vol. 69 Issue 1 Pg. 45-51 (Jul 2008) ISSN: 1365-2265 [Electronic] England
• PMID: 18031309 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Obesity Agents
• Apolipoprotein B-100
• Cholesterol, VLDL
• Heptanoic Acids
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Membrane Proteins
• Membrane Transport Proteins
• NPC1L1 protein, human
• Pyrroles
• Atorvastatin

Topics

• Adult
• Anti-Obesity Agents (therapeutic use)
• Apolipoprotein B-100 (blood, metabolism)
• Atorvastatin
• Cholesterol, VLDL (blood, metabolism)
• Drug Resistance (genetics)
• Genetic Variation (physiology)
• Genotype
• Heptanoic Acids (therapeutic use)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (therapeutic use)
• Kinetics
• Male
• Membrane Proteins (genetics)
• Membrane Transport Proteins
• Middle Aged
• Obesity (blood, drug therapy, genetics, metabolism)
• Pyrroles (therapeutic use)
• Treatment Outcome