Ezetimibe reduces plasma low-density lipoprotein (LDL) cholesterol by blocking sterol absorption in enterocytes. The NPC1L1 gene product was recently identified as the molecular target for ezetimibe, although functional details are incomplete. We used the non-response phenotype of plasma LDL cholesterol to ezetimibe treatment to ascertain individuals who might have variant NPC1L1. We found that one non-responder to ezetimibe was a compound heterozygote for two rare non-synonymous polymorphisms in NPC1L1 that were absent in normal control subjects. We also characterized other NPC1L1 polymorphisms. While there are many explanations for non-response to medications, our data suggest a possible relationship between NPC1L1 variation and ezetimibe response and further indicate that a non-response phenotype might ascertain subjects with genomic DNA variants that could help define metabolic pathways.
1 Acute SR 58611A (0.25 mg kg 71 ), was eective in reducing the blood glucose response to a glucose tolerance test (GTT) in normal lean (control) and spontaneously obese/diabetic CBA/Ca mice and to be equipotent to 1.25 mg kg 71 glibenclamide in lean mice. 2 Neither brown (BAT) nor white (WAT) adipose tissue lipogenesis was altered by acute SR 58611A (2 ± 8 mg kg 71 ) in lean mice, but both increased signi®cantly at the higher doses in the obese mice. 3 Acute SR 58611A produced a hypoglycaemia 40 min after dosing in lean and obese animals, the duration and potency of which was less than that of glibenclamide. Plasma insulin levels increased 20 min after acute SR 58611A and glibenclamide in lean and obese mice. 4 Chronic treatment (0.25 mg kg 71 , 15 days) with SR 58611A increased its eectiveness in improving glucose tolerance, but did not aect the body weight (BW) or food intake of either lean or obese mice. 5 Acute and chronic SR 58611A prolonged the hypoglycaemic eect of exogenous insulin in lean but not obese mice. 6 In fed and fasted lean mice and in fasted obese mice chronic SR 58611A produced an acute hypoglycaemia 30 min post administration which was greater than after a single dose. 7 SR 58611A maintained its eectiveness in improving glucose tolerance in lean and obese mice over a dosing period of 15 days. The improvement in glucose tolerance was achieved at a dose less than that required to stimulate adipose tissue lipogenesis and which did not aect food intake or body weight.
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