High basal fractional cholesterol synthesis is associated with nonresponse of plasma LDL cholesterol to plant sterol therapy.
BACKGROUND
The cholesterol-lowering effectiveness of plant sterol (PS) therapy is hindered by wide-ranging variability in LDL-cholesterol responsiveness across individuals. To capitalize on the LDL-cholesterol-lowering potential of PS in the clinical setting, it is paramount to characterize the metabolic factors that underlie this heterogeneity of responsiveness.


OBJECTIVE
The objective was to investigate the relation between cholesterol synthesis and plasma LDL-cholesterol reductions in response to PS consumption.


METHODS
We evaluated previously conducted clinical PS interventions incorporating stable-isotope measures of cholesterol synthesis and conducted feeding studies in animal models of response (Syrian Golden hamsters) and nonresponse (C57BL/6J mice) to PS consumption.


RESULTS
From our clinical study population (n = 113), we identified 47 nonresponders (3.73 +/- 1.10% change in LDL cholesterol) and 66 responders (-15.16 +/- 1.04% change in LDL cholesterol) to PS therapy. The basal cholesterol fractional synthesis rate (FSR) as measured by direct deuterium incorporation was 23% higher (P = 0.003) in the nonresponder subgroup than in responders to PS therapy. The basal cholesterol FSR correlated (r = 0.22, P = 0.02) with the percentage change in LDL cholesterol after PS intervention. In support of our clinical observations, nonresponding mice showed a 77% higher (P = 0.001) basal cholesterol FSR than that of responding hamsters. Compared with control mice, PS-fed mice showed an increase in hepatic nuclear sterol regulatory element binding protein 2 abundance (1.3-fold of control, P = 0.04) and beta-hydroxy-beta-methylglutaryl coenzyme A reductase-mRNA expression (2.4-fold of control, P = 0.00).


CONCLUSIONS
The results suggest that subjects with high basal cholesterol synthesis are less responsive to PS treatment than are subjects with low basal cholesterol synthesis.
Rideout
Todd C
TC
Richardson Centre for Functional Foods and Nutraceuticals, Winnipeg, Canada. t_rideout@umanitoba.ca
Harding
Scott V
SV
Mackay
Dylan
D
Abumweis
Suhad S
SS
Jones
Peter Jh
PJ
D000328:Adult; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood* / Q000187:drug effects; D006224:Cricetinae; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010840:Phytosterols / Q000494:pharmacology / Q000627:therapeutic use*; D012313:RNA / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000097:blood
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D010840:Phytosterols; D014280:Triglycerides; D012313:RNA; D002784:Cholesterol