Background:
NPC1L1 is the intestinal sterol transporter that is a target molecule of ezetimibe. It has been reported that the LDL response to ezetimibe treatment is significantly different among NPC1L1 haplotypes. We hypothesized that common variants in NPC1L1 would affect cholesterol absorption from intestine and cholesterol synthesis in liver.
Methods:
Genomic DNAs were extracted from 140 healthy Japanese volunteers with informed consent. Three single nucleotide polymorphisms (SNPs) (1735C>G, 25342A>C, and 27677T>C) were determined by PCR-RFLP method. Plasma concentration of lathosterol (a marker of cholesterol synthesis), and sitosterol, campesterol (markers of cholesterol absorption) were determined by LC-MS/MS for 79 subjects whose plasma was available.
Results:
NPC1L1 genotype frequencies of these SNPs of Japanese were as follows; 1735C/C:0.35, 1735C/G:0.464, 1735G/G:0.186; 25342A/A:0.969, 25342A/C:0.031, 25342C/C:0; 27677T/T:0.969, 27677T/ C:0.031, 27677 C/C:0. There were no significant differences in serum lipids concentration among three groups of 1735C/C, C/G, and G/G. Major haplotype of NPC1L1 in Japanese is 1735C-25342A-27677T, whose frequency is 0.573. Plasma concentration of campesterol of those who have at least one haplotype of 1735C-25342A-27677T is lower than those who dose not have 1735C-25342A-27677T, significantly (4.67±2.15 vs. 6.08±4.08 (p<0.05)).
Conclusion:
NPC1L1 genotype frequencies are very different in Japanese populations from those reported in Caucasians. Those who have NPC1L1 haplotype 1735C-25342A-27677T had lower plasma campesterol concentration, which may indicate that cholesterol absorption is reduced in individuals with NPC1L1 haplotype 1735C-25342A-27677T. This may be the reason why ezetimibe is effective to lower LDL-cholesterol in individuals who lack this haplotype.
Use of NBD-cholesterol to identify a minor but NPC1L1-independent cholesterol absorption pathway in mouse intestine
