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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 [+ or -] 1.10% change in LDL cholesterol) and 66 responders (-15.16 [+ or -] 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. Am J Clin Nutr 2010; 92:41-6. doi: 10.3945/ajcn.2009.29073.

Background: Fish-oil fatty acid esters of plant sterols (FO-PS) were shown to have hypotriglyceridemic and hypocholesterolemic properties in animal models. Objective: The objective of the study was to evaluate the hypolipidemic effects of FO-PS supplementation in healthy hypercholesterolemic persons fed an olive oil (00)-based diet. Design: Twenty-one moderately overweight, hyperlipidemic subjects participated in a semi-randomized, single-blind, 4-period crossover study including 4 experimental isoenergetic diets of 4 wk each and 4-wk intervening washout periods. Diets contained 30% of energy as fat, of which 70% was from extra-virgin OO, and differed only in the supplement oil: OO, fish oil, FO-PS, or sunflower oil esters of plant sterols (SU-PS). Both fish oil and FO-PS provided 5.4 g total eicosapentaenoic and docosahexaenoic acids/d. FO-PS, SU-PS, and OO provided the equivalent of 1.7, 1.7, and 0.02 g free plant sterols/d, respectively. Results: Fish oil and FO-PS resulted in fasting and postprandial plasma triacylglycerol concentrations that were markedly lower than those observed with OO and SU-PS (P = 0.0001), but to a different extent. LDL cholesterol was significantly lower after supplementation with FO-PS and SU-PS than at the end of the control OO diet (P = 0.0031 and 0.0407, respectively). HDL cholesterol was not affected. FO-PS and SU-PS resulted in a lower ratio of total to HDL cholesterol and lower apolipoprotein (apo) B concentrations than did OO and fish oil. The ratio of apoB to apoA was significantly lower after SU-PS consumption than after consumption of OO (P = 0.0126) and fish oil (P = 0.0292). FO-PS and SU-PS resulted in similar ratios of apoB to apoA. HDL2 and the ratio of HDL2 to HDL3 were significantly higher at the end of the FO-PS treatment than at the end of the OO (P = 0.0006), fish oil (P = 0.0036), and SU-PS (P = 0.0016) treatments. Conclusion: Supplementation of an OO-based diet with FO-PS may reduce cardiovascular disease risk more than does supplementation with fish oil or SU-PS. KEY WORDS Apolipoproteins, cardiovascular risk factors, fish oil, LDL cholesterol, HDL cholesterol, n-3 polyunsaturated fatty acids, olive oil, plant sterols, plasma lipids, triacylglycerols

Background: More than 50 studies have reported substantial reductions in plasma lipid concentrations in response to 2-40 mg Cuban sugar cane policosanol (SCP) mixtures/d. However, several animal and human trials conducted outside of Cuba that used non-Cuban mixtures have failed to reproduce the efficacy of policosanols observed in earlier studies. Objective: The objective was to evaluate lipid-modulating actions of the authentic Cuban SCPs on plasma lipids in healthy hypercholesterolemic volunteers. Design: Twenty-one volunteers consumed, under supervision, 10 mg SCPs/d or a placebo incorporated in margarine as an afternoon snack, for a period of 28 d with the use of a randomized, double-blind crossover study design. Subjects maintained their habitual diet and physical activity and were weighed daily throughout the study period. Blood was collected at days 1,2, 28, and 29 of the feeding trial, and lipid concentrations were measured. Results: Body weights did not vary significantly throughout the trial and did not affect plasma lipid values. No significant difference was observed between treatment and control groups in plasma total, LDL-, HDL-cholesterol, and triacylglycerol concentrations. Conclusion: Present results show no beneficial effects of Cuban SCPs on lipid indicators in hypercholesterolemic persons and question the clinical usefulness of policosanol mixtures as cholesterol-lowering neutraceutical agents. KEY WORDS Double-blind crossover study design, sugar cane policosanols, cholesterol-lowering effect, LDL cholesterol, hypercholesterolemic persons

Background: Because of hyperglycemia and hyperinsulinemia, diabetic persons have higher cholesterol synthesis and lower cholesterol absorption rates than do nondiabetic persons. Differences in plant sterol efficacy between diabetic and nondiabetic persons have not been examined. Objective: The objective was to compare the degree of response of plasma lipid concentrations and glycemic control to plant sterol consumption in a controlled diet between hypercholesterolemic type 2 diabetic and nondiabetic subjects. Design: Fifteen nondiabetic subjects and 14 diabetic subjects participated in a double-blinded, randomized, crossover, placebo-controlled feeding trial. The diet included 1.8 g/d of either plant sterols or cornstarch placebo over 21 d, separated by a 28-d washout period. Results: Plant sterol consumption significantly reduced (P < 0.05) LDL-cholesterol concentrations from baseline in both nondiabetic and diabetic subjects by 15.1% and 26.8%, respectively. The diabetic subjects had significantly (P < 0.05) lower absolute concentrations of total cholesterol after treatment than did the nondiabetic subjects; however, there was no significant difference in the percentage change from the beginning to the end of the trial. There was also a significant decrease (P < 0.05) in absolute non-HDL-cholesterol concentrations after treatment in both groups. Conclusions: The results showed that plant sterols are efficacious in lowering LDL cholesterol and non-HDL cholesterol in both diabetic and nondiabetic persons. Plant sterol consumption may exist as a dietary management strategy for hypercholesterolemia in persons with type 2 diabetes. KEY WORDS Hypercholesterolemia, type 2 diabetes, plant sterols, cholesterol

Background: Plant sterol supplementation was shown to reduce total and LDL-cholesterol concentrations, whereas endurance training was shown to increase HDL-cholesterol concentrations and decrease triacylglycernl concentrations. Objective: The objective was to examine the effect of plant sterols, endurance training, and the combination of plant sterols and endurance training on plasma lipid and lipoprotein cholesterol concentrations, sterol concentrations, and cholesterol precursor concentrations in previously sedentary hypercholesterolemic adults. Design: In an 8-wk, placebo-controlled, parallel-arm clinical trial, 84 subjects were randomly assigned to receive 1 of 4 interventions: 1) combination of sterols and exercise, 2) exercise, 3) sterols, or 4) control treatment. Results: Sterol supplementation significantly (P < 0.01) decreased total cholesterol concentrations by 8.2% from baseline. In addition, sterols significantly (P < 0.01) lowered absolute LDL-cholesterol concentrations after treatment but had no effect on the percentage change from the beginning to the end of the trial. Exercise significantly (P < 0.01) increased HDL-cholesterol concentrations by 7.5% and decreased triacylglycerol concentrations by 13.3% from baseline. Moreover, sterol supplementation significantly (P < 0.05) increased lathosterol, campesterol, and [beta]-sitosterol concentrations after treatment. Exercise significantly (P < 0.01) decreased percentage of body fat by 3.9% from the beginning to the end of the trial. Conclusions: In comparison with plant sterols or exercise alone, the combination of plant sterols and exercise yields the most beneficial alterations in lipid profiles. Implementation of such a combination therapy could improve lipid profiles in those at risk of coronary artery disease. Am J Clin Nutr 2004;80:1159-66. KEY WORDS Plant sterols, exercise, LDL cholesterol, HDL cholesterol, hypercholesterolemia, sedentary humans

Conjugated linoleic acid (CLA) is a group of positional and geometric isomers of conjugated dienoic derivatives of linoleic acid. The major dietary source of CLA for humans is ruminant meats, such as beef and lamb, and dairy products, such as milk and cheese. The major isomer of CLA in natural food is cis-9,trans-11 (c9, tl1). The commercial preparations contain approximately equal amounts of c9, t11 and trans-10,cis-12 (t10, c12) isomers. Studies have shown that CLA, specifically the t I 0,c12-isomer, can reduce fat tissue deposition and body lipid content but appears to induce insulin resistance and fatty liver and spleen in various animals. A few human studies suggest that CLA supplementation has no effect on body weight and could reduce body fat to a much lesser extent than in animals. To draw conclusions on this form of dietary supplementation and to ultimately make appropriate recommendations, further human studies axe required. The postulated antiobesity mechanisms of CLA include decreased energy and food intakes, decreased lipogenesis, and increased energy expenditure, lipolysis, and fat oxidation. This review addresses recent studies of the effects of CLA on lipid metabolism, fat deposition, and body composition in both animals and humans as well as the mechanisms surrounding these effects. KEY WORDS Conjugated linoleic acid, body weight, fat deposition, body composition, mechanisms, animals, humans

We tested the hypothesis that aging affects whole-body protein turnover via altered fat-free mass (FFM). Whole-body protein kinetics were estimated by the 60-h oral [[sup.15]N]glycine method. Results from 16 healthy, elderly subjects (8 men and 8 women with a mean age of 72.6 y) were compared for age and sex effects with those of 15 lean young subjects (8 men and 7 women with a mean age of 28.4 y) during isoenergetic formula diets. Per kilogram body weight, nitrogen flux was lower only as an effect of age (P = 0.006) whereas age and female sex significantly lowered synthesis and breakdown (P [is less than or equal to] 0.04). However, per kilogram FFM, no significant age or sex effects on rates of protein kinetics remained. Age and female sex contributed significantly to decreased muscle protein catabolism (based on 3-methylhistidine excretion), both in absolute terms and as a percentage of whole-body protein breakdown in the elderly compared with the young: 20.2% compared with 30.9% in women and 27.9% compared with 39.8% in men. No significant age or sex effects on rates of nonmuscle lean tissue protein breakdown were observed with or without correction for body composition. We conclude that the lower rates of flux, synthesis, and breakdown per kilogram body weight in elderly compared with young persons are due to changes in body composition with aging because rates are not different per kilogram FFM. However, there is a reduced contribution by muscle to whole-body protein catabolism in older persons. This has potential implications for the nutrition of both normal and sick elderly persons.

Biosynthesis of cholesterol represents a major input into whole-body pools; however, its regulation has been difficult to study in humans because of limitations in methodologies. The present objectives are to compare available techniques for measuring this process and examine how dietary factors alter human cholesterol biosynthesis. Review of existing techniques suggests that mass isotopomer distribution analysis and deuterium incorporation approaches offer advantages over other methods. Dietary factors influencing human cholesterol synthesis include energy restriction, meal frequency, dietary fat type, and cholesterol and phytosterol content. Food deprivation for as short as 24 h results in almost complete cessation of cholesterol biosynthesis. Similarly, increased meal frequency patterns are associated with a substantial depression in synthesis. In contrast, consumption of oils rich in polyunsaturated fatty acids, despite reducing circulating concentrations, increases the cholesterol synthesis rate compared with other fats. Stepwise addition of dietary cholesterol is associated with only a modest decline in cholesterogenesis while raising plasma concentrations slightly. It can be concluded that synthesis, as a contributor to circulating cholesterol concentrations, is sensitive to many dietary factors. Energy deprivation results in the greatest decline in synthesis, likely accounting for the beneficial decline in circulating cholesterol concentrations observed with weight loss. Am J Clin Nutr 1997;66:438-46.

To assess the influence of dietary fat composition on rates of oxidation of dietary myristic (MA) and palmitic (PA) acids, eight healthy males consumed prepared solid-food diets for 11 d with 40% of total energy as fat. Fifty-five percent of the energy obtained in the form of fat was provided as butter or beef tallow. On days 8 and 11 of each diet cycle, 20 mg/kg body wt of either [[1.sup.-13] C]MA or [[1.sup.-13]C]PA was ingested with breakfast. Hourly breath samples were collected over 9 h thereafter and [sup.13][CO.sub.2] enrichments were determined by using isotope-ratio mass spectrometry. The percentage of [sup.13]C]MA appearing in breath carbon dioxide over 9 h was more than twofold that of PA (P

To examine meal-frequency effects on circulating hormone concentrations and cholesterol synthesis, male subjects consumed liquid diets given as either six evenly spaced (ES) or three diurnal (DI) meals over 3 d. Deuterium oxide was given on day 2 and blood sampled every 4 h over days 2 and 3 to measure plasma cholesterol, glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) concentrations and cholesterol synthesis. Cholesterol synthesis was determined from deuterium incorporation into plasma free cholesterol by using constrained and unconstrained curve-fit models. Plasma total cholesterol concentrations decreased in both ES and DI groups (P < 0.05). The ES group had lower insulin (P < 0.05) and GIP (P < 0.001) concentrations compared with the DI group. Cholesterol synthesis was reduced (P < 0.01) in the ES vs the DI group when determined by using constrained (0.050 [+ or -] 0.002 vs 0.075 [+ or -] 0.005 pools/d, respectively) and unconstrained (0.072 [+ or -] 0.005 vs 0.119 [+ or -] 0.011 pools/d, respectively) models. These data suggest meal frequency-dependent control of cholestero-genesis via hormonally mediated mechanisms.

Manufactured infant formulas have a much lower cholesterol content than breast milk. Cholesterol is required for many body functions, including maintenance of the membranes that surround every cell. Levels of dietary cholesterol may affect intestinal cholesterol production; the intestines, as well as the liver, have the ability to make cholesterol. The effect of differing levels of dietary cholesterol on cholesterol production by the liver and intestines was investigated in newborn piglets. The physiology of pigs closely resembles that of humans in crucial areas. In all piglets, plasma (blood) cholesterol levels rose with age, but plasma cholesterol levels were higher in breast milk (BM)-fed animals on days 15 and 25 postpartum than in formula-fed animals. In animals fed formula, cholesterol synthesis by the liver increased as a response to their low cholesterol diet, while intestinal cholesterol synthesis was not affected. The cholesterol synthesis in the livers of BM-fed animals was low, presumably because their diets supplied more cholesterol. In addition, cholesterol contained in intestinal cells was depleted following birth, probably for use in making bile acids and other important body compounds. The results indicate that in newborn piglets, liver cholesterol production can compensate for low cholesterol levels in the diet. (Consumer Summary produced by Reliance Medical Information, Inc.)