Dylan S. MacKay

Progress and prospective of plant sterol and plant stanol research: Report of the Maastricht meeting.

Abundant evidence over past decades shows that foods with added plant sterols and plant stanols lower serum LDL cholesterol concentrations. However, despite the overwhelming data, numerous scientific questions still remain. The objective of this paper is to summarize the considerations of 60 academic and industrial experts who participated in the scientific meeting in Maastricht, the Netherlands, on issues related to the health effects of plant sterols and plant stanols. The meeting participants discussed issues including efficacy profiling, heterogeneity in responsiveness, effects beyond LDL-C lowering, and food formulation aspects of plant sterol and stanol consumption. Furthermore, aspects related to the potential atherogenicity of elevated circulatory plant sterol concentrations were discussed. Until the potential atherogenicity of plant sterols is resolved, based on the results >200 clinical trials, the risk to benefit of plant sterol use is favorable. Evidence on these topics in plant sterol and plant stanol research was presented and used to reach consensus where possible. It was concluded that endpoint studies looking at plant sterol and plant stanol efficacy are needed, however, there was no clear opinion on the best marker and best design for such a study. Based on the current scientific evidence, plant sterols and plant stanols are recommended for use as dietary options to lower serum cholesterol.

Nonnutritive sweeteners and cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies.

BACKGROUND Nonnutritive sweeteners, such as aspartame, sucralose and stevioside, are widely consumed, yet their long-term health impact is uncertain. We synthesized evidence from prospective studies to determine whether routine consumption of non-nutritive sweeteners was associated with long-term adverse cardiometabolic effects. METHODS We searched MEDLINE, Embase and Cochrane Library (inception to January 2016) for randomized controlled trials (RCTs) that evaluated interventions for nonnutritive sweeteners and prospective cohort studies that reported on consumption of non-nutritive sweeteners among adults and adolescents. The primary outcome was body mass index (BMI). Secondary outcomes included weight, obesity and other cardiometabolic end points. RESULTS From 11 774 citations, we included 7 trials (1003 participants; median follow-up 6 mo) and 30 cohort studies (405 907 participants; median follow-up 10 yr). In the included RCTs, nonnutritive sweeteners had no significant effect on BMI (mean difference −0.37 kg/m2; 95% confidence interval [CI] −1.10 to 0.36; I2 9%; 242 participants). In the included cohort studies, consumption of nonnutritive sweeteners was associated with a modest increase in BMI (mean correlation 0.05, 95% CI 0.03 to 0.06; I2 0%; 21 256 participants). Data from RCTs showed no consistent effects of nonnutritive sweeteners on other measures of body composition and reported no further secondary outcomes. In the cohort studies, consumption of nonnutritive sweeteners was associated with increases in weight and waist circumference, and higher incidence of obesity, hypertension, metabolic syndrome, type 2 diabetes and cardiovascular events. Publication bias was indicated for studies with diabetes as an outcome. INTERPRETATION Evidence from RCTs does not clearly support the intended benefits of nonnutritive sweeteners for weight management, and observational data suggest that routine intake of nonnutritive sweeteners may be associated with increased BMI and cardiometabolic risk. Further research is needed to fully characterize the long-term risks and benefits of nonnutritive sweeteners. Protocol registration: PROSPERO-CRD42015019749

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. DESIGN 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). CONCLUSION The results suggest that subjects with high basal cholesterol synthesis are less responsive to PS treatment than are subjects with low basal cholesterol synthesis.

Plasma noncholesterol sterols: current uses, potential and need for standardization.

Purpose of review Noncholesterol sterols (NCSs) in plasma encompass endogenous cholesterol precursors and exogenous phytosterols and cholesterol metabolites, which are used as surrogate measures of cholesterol synthesis and cholesterol absorption, respectively. The ratios of cholesterol synthesis to cholesterol absorption surrogates are also utilized to assess the overall balance of cholesterol metabolism, with higher values representing more synthesis and lower values more absorption. The objective of this review is to focus on recent findings using plasma NCSs and their potential in customizing dietary and pharmacological hypolipidemic therapies. Recent findings NCSs are often used to assess the impact of pharmacological and dietary interventions on cholesterol metabolism. Various forms of dyslipidemia have been characterized using NCSs, and NCSs may be a valuable tool in selecting appropriate treatment therapies. NCSs levels are affected by genetic, dietary and physiological factors and have been related to cardiovascular disease risk. Summary The expanded use of plasma NCSs is currently limited by the lack of standardized methodology. However, noncholesterol sterols are still a valuable research tool for the overall assessment of cholesterol metabolism and may have clinical potential in the personalization of diet and medicine.

Early Exposure to Nonnutritive Sweeteners and Long-term Metabolic Health: A Systematic Review.

CONTEXT: Nonnutritive sweetener (NNS) consumption is increasing among children, yet its long-term health impact is unclear, particularly when exposure occurs during early life. OBJECTIVE: To synthesize evidence from prospective studies evaluating the association of early-life NNS exposure and long-term metabolic health. DATA SOURCES: Medline, Embase, and Cochrane Library (inception to July 2015). STUDY SELECTION: We aimed to include randomized controlled trials (RCTs) evaluating NNS-based interventions and prospective cohort studies reporting NNS exposure among pregnant women, infants, or children (<12 years of age), with a minimum study duration of 6 months. DATA EXTRACTION: The primary outcome was BMI; secondary outcomes included growth velocity, overweight/obesity, adiposity, and adverse metabolic effects. Study quality and risk of bias were evaluated using validated assessment tools. RESULTS: We identified 6 eligible cohort studies and 2 RCTs (n = 15 641 children). Half of the cohorts reported increasing weight gain or fat mass accumulation with increasing NNS intake, and pooled data from 2 cohorts showed a significant correlation with BMI gain (weighted mean correlation 0.023, 95% confidence interval 0.006 to 0.041). RCTs reported contradictory effects on weight change in children receiving NNSs. No eligible studies evaluated prenatal or infant NNS exposure. LIMITATIONS: Meta-analysis was limited because of the small number of eligible studies and heterogeneity of populations and outcomes. CONCLUSIONS: There is limited and inconsistent evidence of the long-term metabolic effects of NNS exposure during gestation, infancy, and childhood. Further research is needed to inform recommendations for the use of NNSs in this sensitive population.

Evaluation of methods for the determination of cholesterol absorption and synthesis in humans

Cardiovascular disease risk and its associated complications correlate positively with circulating cholesterol levels. Plasma cholesterol levels are maintained by reciprocally related endogenous cholesterol synthesis and cholesterol absorption from dietary and biliary sources. Numerous in vivo clinical methods exist to quantify the absorption and synthesis of cholesterol in humans. This review summarizes these different methods available to study cholesterol absorption and synthesis, highlighting each methods strengths and weaknesses, as well as their applicability in different types of trials.

Methodological considerations for the harmonization of non-cholesterol sterol bio-analysis

Non-cholesterol sterols (NCS) are used as surrogate markers of cholesterol metabolism which can be measured from a single blood sample. Cholesterol precursors are used as markers of endogenous cholesterol synthesis and plant sterols are used as markers of cholesterol absorption. However, most aspects of NCS analysis show wide variability among researchers within the area of biomedical research. This variability in methodology is a significant contributor to variation between reported NCS values and hampers the confidence in comparing NCS values across different research groups, as well as the ability to conduct meta-analyses. This paper summarizes the considerations and conclusions of a workshop where academic and industrial experts met to discuss NCS measurement. Highlighted is why each step in the analysis of NCS merits critical consideration, with the hopes of moving toward more standardized and comparable NCS analysis methodologies. Alkaline hydrolysis and liquid-liquid extraction of NCS followed by parallel detection on GC-FID and GC-MS is proposed as an ideal methodology for the bio-analysis of NCS. Furthermore the importance of cross-comparison or round robin testing between various groups who measure NCS is critical to the standardization of NCS measurement.

Metabolic and genetic factors modulating subject specific LDL-C responses to plant sterol therapy.

Reducing intestinal cholesterol absorption with plant sterol consumption is a well-characterized strategy to lower LDL-C and potentially reduce cardiovascular disease risk. However, over 50 years of clinical research demonstrate that there is significant heterogeneity in the individual LDL-C lowering response to plant sterol therapy. A clear understanding of why plant sterols work effectively in some individuals but not in others will ensure optimal integration of plant sterols in future personalized nutritional lipid-lowering strategies. This review will examine the current knowledge base surrounding the metabolic and genetic determinants of LDL-C lowering in response to plant sterol consumption.

Lathosterol-to-cholesterol ratio in serum predicts cholesterol-lowering response to plant sterol consumption in a dual-center, randomized, single-blind placebo-controlled trial

BACKGROUND 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 nonresponse to PS consumption; however, prospective studies that show this association have yet to be conducted. OBJECTIVE The goal was to test whether the lathosterol-to-cholesterol ratio (L:C ratio), a surrogate marker of endogenous cholesterol synthesis, serves as an a priori predictor of cholesterol lowering in response to PS consumption. DESIGN Sixty-three mildly hypercholesterolemic adults who were preselected as possessing either high endogenous cholesterol synthesis [HS; n = 24; L:C = 2.03 ± 0.39 μmol/mmol (mean ± SD)] or low endogenous cholesterol synthesis (LS; n = 39; L:C = 0.99 ± 0.28 μmol/mmol) on the basis of baseline L:C consumed 2 g PS/d or a placebo for 28 d with the use of a dual-center, single-blind, randomized crossover design. Plasma lipid and noncholesterol sterol concentrations were measured at the end of each phase. RESULTS PS consumption lowered total cholesterol (TC; -0.25 ± 0.05 mmol/L; P < 0.0001) and LDL cholesterol (-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 cholesterol (-0.29 ± 0.05 mmol/L; P = 0.0002), whereas HS individuals failed to show cholesterol lowering (TC: -0.09 ± 0.09 mmol/L; P = 0.2843; LDL cholesterol: -0.05 ± 0.07 mmol/L; P = 0.4917). The odds of LS participants responding to PS consumption with cholesterol lowering better than the mean cholesterol lowering in all participants were 4.25 (95% CI: 1.242, 14.556; P = 0.0211) for TC and 3.36 (95% CI: 1.112, 10.161; P = 0.0317) for LDL cholesterol, which was higher than for HS participants. CONCLUSIONS The L:C ratio predicts the extent of reduction in circulating TC and LDL cholesterol in response to PS consumption. Cholesterol synthesis assessment may thus have a use in identifying responders and nonresponders to PS therapy.

Glucose tolerance is affected by visceral adiposity and sex, but not birth weight, in Yucatan miniature pigs

Epidemiological studies have linked small birth weight and lack of breastfeeding to type 2 diabetes mellitus. This study aimed to determine if (i) small birth weight promotes and (ii) suckling prevents the development of adiposity and diabetes biomarkers in a Yucatan miniature pig model. At 3 days of age, the intrauterine growth-restricted (IUGR) piglet (n = 6) was paired with a normal weight (NW), same-sex littermate (n = 6) and fed milk replacer for 4 weeks. A sow-fed normal weight littermate (n = 6) was also compared with the NW littermate to assess the effects of suckling. All pigs were fed a standard diet ad libitum for 5 h·day(-1) from week 4. At 9.5 months, pigs underwent intravenous glucose tolerance (IVGTT) and insulin sensitivity tests (IST). At 10 months, tissues were harvested for fat analysis and pancreas histology. IUGR pigs demonstrated compensatory growth before sexual maturity and had greater subcutaneous fat depth; birth weight also negatively correlated with visceral fat content. Visceral and subcutaneous adiposity were greater in females than males. IVGTT and IST outcomes were not different due to birth weight or suckling. However, visceral adiposity was associated with several glucose tolerance outcomes and females were more glucose intolerant due to their greater adiposity. Pancreas insulin content or histology outcomes were not different. This model did not develop markers of type 2 diabetes mellitus because of small birth weight or formula feeding. However, visceral adiposity and sex were associated with glucose intolerance, which is consistent with data in humans.