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Title:   Author  item
                                            MACKAY, DYLAN - University Of Manitobaitem
                                            Gebauer, Sarahitem
                                            ECK, PETER - University Of Manitobaitem
                                            Baer, Daviditem
                                            JONES, PETER - University Of Manitoba
  Submitted to: The American Journal of Clinical Nutrition
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 12/16/2014
                                    Publication  Date: 3/1/2015
                                    Citation: MacKay, D., Gebauer, S.K., Eck, P., Baer, D.J., Jones, P. 2015. Lathosterol to cholesterol ratio in serum predicts cholesterol lowering response to plant sterol consumption in a dual center, randomized, single-blind placebo controlled trial. American Journal of Clinical Nutrition. 101:432-439.Interpretive Summary: Plant sterols (PS) are naturally occurring products which have been shown to be effective in lower LDL cholesterol yet there is large range in response across individuals.  Using stable isotopes to measure cholesterol synthesis, we have shown that in individuals with higher cholesterol synthesis, there is an association with reduced LDL cholesterol lowering with PS consumption.   A study was conducted to evaluate the effectiveness of blood lathosterol to cholesterol ratio (L/C) which is a surrogate marker of cholesterol synthesis, as a predictor of cholesterol lowering in response to PS consumption.  Sixty-three adults with slightly elevated cholesterol were recruited.  These volunteers also had either a high (n=24, L/C = 2.03 ± 0.39umol/mmol) or low (n=39, L/C =0.99±0.28 umol/mmol) L/C ratio at baseline.  Each volunteer consumed either 0 or 2 g/d (free sterol) of PS ester in margarine for 28 days in a dual-center, single-blind, randomized, crossover design. At the end of each of the two treatment periods (0 or 2 g/d of PS), blood lipid and non-cholesterol sterol levels were measured.  Additionally, volunteers were genotyped for the single nucleotide changes in one gene (rs3808607 in CYP7A1).  As with many previous studies, overall, PS consumption significantly lowered LDL cholesterol.  In this study, we also found that volunteers with a high or low L/C ratio responded differently.  LDL cholesterol was significantly lowered in the low L/C group but not the high L/C group.  We also found that different nucleotides in the rs3808607 in CYP7A1 showed a significant interaction with PS consumption and LDL cholesterol response.  LDL cholesterol was significantly lowered in the G/T and G/G gene structure but not the T/T gene structure.  The L/C ratio predicts reductions in LDL-C in response to PS consumption, and gene structure influences response to PS consumption. Both cholesterol synthesis level and gene rs3808607 genotype may have clinical use in identifying responders and non-responders to PS therapy.  These data are important to physicians, dieticians, and allied health care professionals providing dietary recommendations on the use of PS to lower cholesterol as well as individuals interested in using already available PS containing foods to control elevated LDL cholesterol.
                                Technical Abstract: Benefits of plant sterols (PS) for cholesterol lowering are compromised by large variability in efficacy across individuals. High fractional cholesterol synthesis measured by deuterium incorporation has been associated with non-response to PS consumption; however, prospective studies showing this association have yet to be conducted. The goal was to test whether lathosterol to cholesterol ratio (L/C), a surrogate marker of endogenous cholesterol synthesis, serves as an a priori predictor of cholesterol lowering in response to PS consumption.  Sixty three mildly hypercholesterolemic adults pre-selected as possessing either high endogenous cholesterol synthesis (HS, n=24, L/C = 2.03 ± 0.39umol/mmol) or low endogenous cholesterol synthesis (LS, n=39, L/C =0.99±0.28 umol/mmol) based on baseline L/C ratio, consumed 2g/d of PS or a placebo for 28 days using a dual-center, single-blind, randomized, crossover design. Plasma lipid and non-cholesterol sterol levels were measured at the end of each phase.   PS consumption lowered total cholesterol (TC,-0.25 ±0.05 mmol/L, p <0.0001) and LDL cholesterol (LDL-C, -0.17 ± 0.04 mmol/L, p<0.0001) overall. Specifically, LS individuals responded to PS treatment with a reduction in TC (-0.40 ± 0.07 mmol/L, p<0.0001) and LDL-C (-0.29 ±0.05 mmol/L, p=0.0002), while HS individuals failed to show a cholesterol-lowering response (TC, -0.09±0.09 mmol/L, p=0.2843 and LDL-C, -0.05±0.07 mmol/L, p=0.4917). The odds of LS participants responding, with cholesterol lowering, to PS consumption were 4.25 (95%CL 1.242 -14.556, p=0.0211) for TC, and 3.36 (95%CL 1.112 -10.161, p=0.0317) for LDLC, higher than HS participants. The L/C ratio predicts the extent of reduction in 23 circulating TC and LDL-C in response to PS consumption. Cholesterol synthesis assessment may thus have a use in identifying responders and non-responders to PS therapy.


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