Glucosamine effects in humans: a review of effects on glucose metabolism, side effects, safety considerations and efficacy.

Glucosamine is widely used to relieve symptoms from osteoarthritis. Its safety and effects on glucose metabolism are critically evaluated in this review. The LD50 of oral glucosamine in animals is approximately 8000 mg/kg with no adverse effects at 2700 mg/kg for 12 months. Because altered glucose metabolism can be associated with parenteral administration of large doses of glucosamine in animals and with high concentrations in in vitro studies, we critically evaluated the clinical importance of these effects. Oral administration of large doses of glucosamine in animals has no documented effects on glucose metabolism. In vitro studies demonstrating effects of glucosamine on glucose metabolism have used concentrations that are 100-200 times higher than tissue levels expected with oral glucosamine administration in humans. We reviewed clinical trial data for 3063 human subjects. Fasting plasma glucose values decreased slightly for subjects after oral glucosamine for approximately 66 weeks. There were no adverse effects of oral glucosamine administration on blood, urine or fecal parameters. Side effects were significantly less common with glucosamine than placebo or non-steroidal anti-inflammatory drugs (NSAID). In contrast to NSAID, no serious or fatal side effects have been reported for glucosamine. Our critical evaluation indicates that glucosamine is safe under current conditions of use and does not affect glucose metabolism.

Dietary effects on cardiovascular disease risk factors: beyond saturated fatty acids and cholesterol.

Hypercholesterolemia represents a significant risk for cardiovascular disease (CVD). While diet intervention remains the initial choice for the prevention and treatment of CVD, the nature of the dietary modification remains controversial. For example, reducing calories from total fat, without decreasing saturated fat intake results in insignificant changes in low density lipoprotein cholesterol (LDL-C). Similarly, diet interventions that focus solely on lowering dietary cholesterol and saturated fat intake not only decrease LDL-C, but also high density lipoprotein cholesterol (HDL-C) and therefore may not improve the lipoprotein profile. This brief review summarizes dietary interventions that lower LDL-C without affecting HDL-C levels. These interventions include soy protein, soluble fiber, soy lecithin and plant sterols. This review also includes some of the reported dietary interventions, such as polyphenols, isoflavones, folic acid and vitamins B6 and B12, which reduce the risk of CVD without changes in lipoprotein cholesterol.

Trans fatty acids and cardiovascular risk.

Trans fatty acids are found in partially hydrogenated vegetable oil, in meats, and in dairy products. Their effect on blood cholesterol concentrations was examined decades ago, but recently there has been renewed interest in understanding how trans fatty acids affect blood lipids and lipoprotein cholesterol concentrations. Current advice to reduce cardiovascular disease (CVD) risk includes decreasing the consumption of saturated and total fat to help manage blood cholesterol concentrations. Saturated fat contributes significantly to total fat intake and markedly raises blood cholesterol concentrations. Trans fatty acids, which are consumed in much smaller quantities, have been shown to be modestly hypercholesterolemic in studies that have substituted hydrogenated vegetable oils for unhydrogenated oils. In contrast, when partially hydrogenated vegetable oils containing trans fatty acids are substituted for cholesterol-raising saturated fats, blood cholesterol levels are reduced. Partially hydrogenated vegetable oils are used in place of saturated fat in many food products. These foods can help consumers lower their saturated fat intake to achieve dietary recommendations. The following review critically examines the role of hydrogenated fats in the food supply, the metabolism of trans fatty acids, and the scientific literature surrounding the effects of partially hydrogenated vegetable oils and trans fatty acids on blood cholesterol concentrations and cardiovascular disease risk.

Comparative cholesterol lowering properties of vegetable oils: beyond fatty acids.

OBJECTIVE: Our laboratory has previously reported that the hypolipidemic effect of rice bran oil (RBO) is not entirely explained by its fatty acid composition. Although RBO has up to three times more serum cholesterol-raising saturated fatty acids (SATS) than some unsaturated vegetable oils, we hypothesized that its greater content of the unsaponifiables would compensate for its high SATS and yield comparable cholesterol-lowering properties to other vegetable oils with less SATS. METHODS: To study the comparative effects of different unsaturated vegetable oils on serum lipoprotein levels, nine cynomologus monkeys (Macaca fascicularis) were fed diets, for four weeks, in a Latin square design, containing rice bran, canola or corn oils (as 20% of energy) in a basal mixture of other fats to yield a final dietary fat concentration of 30% of energy. All animals were fed a baseline diet containing 36% of energy as fat with 15% SATS, 15% monounsaturated fatty acids (MONOS) and 6% polyunsaturated fatty acids (POLYS). RESULTS: Despite the lower SATS and higher MONOS content of canola oil and the higher POLYS content of corn oil, RBO produced similar reductions in serum total cholesterol (TC) (-25%) and low density lipoprotein cholesterol (LDL-C) (-30%). In addition, as compared to the baseline diet, the reduction in serum TC and LDL-C cholesterol with RBO was not accompanied by reductions in high density lipoprotein cholesterol (HDL-C) which occurred with the other two dietary oils. Using predictive equations developed from data gathered from several studies with non-human primates, we noted that the observed serum TC and LDL-C lowering capabilities of the RBO diet were in excess of those predicted based on the fatty acid composition of RBO. CONCLUSIONS: These studies suggest that non-fatty acid components (unsaponifiables) of RBO can contribute significantly to its cholesterol-lowering capability.

Soy lecithin reduces plasma lipoprotein cholesterol and early atherogenesis in hypercholesterolemic monkeys and hamsters: beyond linoleate.

The current study was designed to investigate the hypocholesterolemic and anti-atherogenic properties of soy lecithin beyond its fatty acid content. In experiment 1, 18 cynomolgus monkeys were divided into three groups of six and fed diets which approximated either the average American diet (AAD), the American Heart Association (AHA) Step I diet, or a modified AHA (mAHA) Step I diet containing 3.4% soy lecithin for 8 weeks. Plasma samples were collected from food-deprived monkeys and analyzed for total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), very low- and low-density lipoprotein cholesterol (non-HDL-C), and triglyceride (TG) concentrations. Group comparisons revealed that monkeys fed the mAHA Step 1 diet had significantly lower plasma TC (-46%) and non-HDL-C (-55%) levels compared to the AAD diet, whereas monkeys fed the AHA Step 1 diet had lesser reductions in plasma TC (-21%) and non-HDL-C (-18%) levels. The monkeys fed the mAHA Step I diet had significantly lower plasma TC (-32%) and non-HDL-C (-45%) compared to the monkeys fed the AHA step diet. Also, only the mAHA Step I diet significantly reduced pre-treatment plasma TC and non-HDL-C levels by - 39 and -51% respectively with no significant effect on plasma HDL-C or TG levels. In experiment 2, 45 hamsters were divided into three groups of 15 and fed the following three modified non-purified diets for 8 weeks: a hypercholesterolemic diet (HCD) containing 10%, coconut oil and 0.05%, cholesterol, HCD plus 3.4%, soy lecithin (+SL), or the HCD with added levels of linoleate and choline equivalent to the +SL diet but no lecithin (-SL). Plasma lipids were determined as in experiment 1 and aortas were perfusion-fixed and Oil Red O stained for morphometric analyses of fatty streak area. Relative to the HCD group, the +SL-treated hamsters had significantly lower plasma TC (-58%), non-HDL-C (-73%) and aortic fatty streak area (-90%). Relative to the -SL group, hamsters fed the +SL diet had significantly lower plasma TC (-33%), non-HDL-C (-50%) and significantly reduced aortic fatty streak area (-79%). In conclusion, the first experiment suggests that the cholesterol-lowering efficacy of the AHA Step I diet can be enhanced with the addition of soy lecithin without reducing plasma HDL-C levels. whereas the second experiment suggest that the hypocholesterolemic, and in particular, the anti-atherogenic properties of soy lecithin cannot be attributed solely to its linoleate content.

Regulation of plasma lipoprotein levels by dietary triglycerides enriched with different fatty acids.

Saturated vegetable oils (coconut, palm, and palm kernel oil) containing predominantly saturated fatty acids, lauric (12:0) or myristic (14:0 and palmitic (16:0), raise plasma total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels in animals and humans, presumably by decreasing LDL receptor activity and/or increasing LDL-C production rate. Although stearic acid (18:0) is chemically a saturated fatty acid, both human and animal studies suggest it is biologically neutral (neither raising nor lowering) blood cholesterol levels. Although earlier studies indicated that medium chain fatty acids (8:0-10:0) were also thought to be neutral, more recent studies in animals and humans suggest otherwise. Unsaturated vegetable oils such as corn, soybean, olive, and canola oil, by virtue of their predominant levels of either linoleic acid (18:2) or oleic acid (18:1), are hypocholesterolemic, probably as a result of their ability to upregulate LDL receptor activity and/or decrease LDL-C production rate. Whether trans fatty acids such as trans oleate (t18:1), in hydrogenated products such as margarine, are hypercholesterolemic remains controversial. Studies in humans suggest that their cholesterol-raising potential falls between the native nonhydrogenated vegetable oil and the more saturated dairy products such as butter. Assessment of the magnitude of the cholesterolemic response of trans 18:1 is difficult because in most diet studies its addition is often at the expense of cholesterol-lowering unsaturated fatty acids, making an independent evaluation almost impossible.

Dietary fat saturation effects on low-density-lipoprotein concentrations and metabolism in various animal models.

Saturated vegetable oils (coconut, palm, and palm kernel oil) and fats (butter and lard) are hypercholesterolemic relative to monounsaturated and polyunsaturated vegetable oils. The increase in plasma low-density-lipoprotein-cholesterol (LDL-C) concentrations associated with consumption of saturated vegetable oils and fats is largely explained by a decrease in hepatic LDL receptor activity and an increase in the LDL-C production rate. Hepatic LDL receptor activity may be regulated by the messenger RNA concentration of the LDL receptor. The decrease in hepatic LDL receptor activity with saturated fat feeding is associated with decreased hepatic sterol O-acyltransferase activity and, therefore, a reduced inert pool of cholesteryl ester. A putative regulatory pool of cholesterol is increased with saturated fat feeding and suppresses LDL receptor activity, possibly through hepatic messenger RNA regulation. For most studies, an independent effect of a vegetable oil or fat could not be ascertained because there was no neutral control and at least two of the test oils or fats were varied. Animal data for the effects of individual fatty acids on plasma LDL-C concentrations and metabolism are sparse. The evidence suggests that caproic acid (6:0), caprylic acid (8:0), and capric acid (10:0) are neutral with respect to their LDL-C-raising properties and their ability to modulate LDL metabolism. Lauric acid (12:0), myristic acid (14:0), and palmitic acid (16:0) are approximately equivalent in their LDL-C-raising potential by reducing hepatic LDL receptor activity and increasing the LDL-C production rate, apparently via modulation of sterol O-acyltransferase activity. Stearic acid (18:0) appears to be neutral in its LDL-C-raising potential and how it affects LDL metabolism.

Oryzanol decreases cholesterol absorption and aortic fatty streaks in hamsters.

Oryzanol is a class of nonsaponifiable lipids of rice bran oil (RBO). More specifically, oryzanol is a group of ferulic acid esters of triterpene alcohol and plant sterols. In experiment 1, the mechanisms of the cholesterol-lowering action of oryzanol were investigated in 32 hamsters made hypercholesterolemic by feeding chow-based diets containing 5% coconut oil and 0.1% cholesterol with or without 1% oryzanol for 7 wk. Relative to the control animals, oryzanol treatment resulted in a significant reduction in plasma total cholesterol (TC) (28%, P < 0.01) and the sum of IDL-C, LDL-C, and VLDL-C (NON-HDL-C) (34%, P < 0.01). In addition, the oryzanol-treated animals also exhibited a 25% reduction in percent cholesterol absorption vs. control animals. Endogenous cholesterol synthesis, as measured by the liver and intestinal HMG-CoA reductase activities, showed no difference between the two groups. To determine whether a lower dose of oryzanol was also efficacious and to measure aortic fatty streaks, 19 hamsters in experiment 2 were divided into two groups and fed for 10 wk chow-based diets containing 0.05% cholesterol and 10% coconut oil (w/w) (control) and the control diet plus 0.5% oryzanol (oryzanol). Relative to the control, oryzanol-treated hamsters had reduced plasma TC (44%, P < 0.001), NON-HDL-C (57%, P < 0.01), and triglyceride (TG) (46%, P < 0.05) concentrations. Despite a 12% decrease in high density lipoprotein cholesterol (HDL-C) (P < 0.01), the oryzanol-treated animals maintained a more optimum NON-HDL-C/HDL-C profile (1.1 +/- 0.4) than the control (2.5 +/- 1.4; P < 0.0075). Aortic fatty streak formation, so defined by the degree of accumulation of Oil Red O-stained macrophage-derived foam cells, was reduced 67% (P < 0.01) in the oryzanol-treated animals. From these studies, it is concluded that a constituent of the non-saponifiable lipids of RBO, oryzanol, is at least partially responsible for the cholesterol-lowering action of RBO. In addition, the cholesterol-lowering action of oryzanol was associated with significant reductions in aortic fatty streak formation.

Immunologic effects of marine- and plant-derived n-3 polyunsaturated fatty acids in nonhuman primates.

The effect of marine- and plant-derived n-3 polyunsaturated fatty acids (PUFAs) on T cell-mediated immune response was studied in cynomolgus monkeys. Animals were first fed a 14-wk baseline diet; 10 animals were then fed diets containing 1.3% or 3.3% of energy as eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) which the other 10 were fed diets containing 3.5% or 5.3% of energy as alpha-linolenic acid (ALA) for two consecutive 14-wk periods. Both diets significantly decreased the percentage of T cells (except 1.3% EPA + DHA), T helper cells (except 1.3% EPA + DHA and 3.5% ALA), and T suppressor cells. Proliferative response of lymphocytes to T cell mitogens significantly increased after the diet containing 3.3% EPA + DHA. Interleukin 2 production significantly increased after the diets containing 1.3% and 3.3% EPA + DHA. No significant changes in mitogenic response or interleukin 2 production were found after ALA diets. Feeding 1.3% or 3.3% EPA + DHA or 5.3% ALA significantly suppressed prostaglandin E2 production in response to T cell mitogens. Plasma tocopherol concentrations were decreased significantly only in monkeys fed ALA diets. We conclude that after adjustment for the tocopherol concentration, marine-derived n-3 PUFAs but not plant-derived n-3 PUFAs increased T cell-mediated mitogenic response and interleukin 2 production. This is most likely due to diet-induced quantitative differences in cellular fatty acid composition and, thus, in prostaglandin E2 production and tocopherol status.

Coffee oil consumption does not affect serum cholesterol in rhesus and cebus monkeys.

Oil from coffee beans contains the diterpenes cafestol and kahweol, which greatly elevate cholesterol in humans. Consumption of 0.03 g coffee oil (0.86 mg cafestol and 1.04 mg kahweol)/kg body wt raised serum cholesterol by 1.27 mmol/L in volunteers. We fed coffee oil from this same batch to cebus and rhesus monkeys. Two groups of eight cebus monkeys were fed a purified diet containing 0.5% coffee oil or placebo oil (sunflower plus palm oil, 3:2, wt/wt) for 2 x seven and a half weeks in a crossover design. The daily intake of the coffee oil was 0.18 g (5.13 mg cafestol and 6.21 mg kahweol)/kg body wt, or sixfold that in the human study. Coffee oil did not affect plasma cholesterol or triglyceride concentrations compared with the placebo oil. Two groups of three rhesus monkeys were fed a commercial diet containing either 0.5% coffee oil or 0.5% placebo oil for 2 x 6 wk in a crossover design. The daily intake of coffee oil was 0.20 g (5.70 mg cafestol and 6.90 mg kahweol)/kg body wt. Again, there was no effect of coffee oil on plasma cholesterol or triglyceride concentrations. Contrary to the findings in human studies, coffee oil had no impact on plasma alanine aminotransferase activity in nonhuman primates. The cholesterol-raising effect of diterpenes from coffee oil, present in boiled coffee, seems to be specific for human primates.

Diets enriched in unsaturated fatty acids enhance apolipoprotein A-I catabolism but do not affect either its production or hepatic mRNA abundance in cynomolgus monkeys.

To determine the mechanisms whereby dietary fatty acids influence high density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I concentrations, ten cynomolgus monkeys were fed each of three experimental diets enriched in saturated (SAT), monounsaturated (MONO), or polyunsaturated (POLY) fatty acids in a crossover design consisting of three 13-week periods, with each animal serving as its own control. Each diet contained 30% of energy as fat with 0.22 mg cholesterol/kcal and differed solely by the isocaloric substitution of fatty acids as 18% of total energy calories. The replacement of dietary saturated fatty acids with either monounsaturated or polyunsaturated fatty acids, respectively, resulted in significant reductions of plasma total cholesterol (-17%; -30%), HDL cholesterol (-32%; -41%), and apo A-I (-37%; -44%) concentrations, while no significant differences were noted in plasma lipid or apo A-I concentrations when the MONO and POLY phases were compared. Although the MONO and POLY diets were similar in their effects on plasma lipids and apolipoproteins, the HDL of monkeys fed the POLY diet, as compared with either the SAT or the MONO diets, contained more cholesteryl ester and phospholipid but less total protein, resulting in a significantly lower total lipid to protein constituent ratio. Metabolic experiments revealed that the significantly lower plasma apo A-I concentrations observed during both the MONO and POLY phases relative to SAT were directly attributable to enhanced HDL apo A-I catabolism. Conversely, neither HDL apo A-I production rates nor hepatic apo A-I mRNA concentrations were significantly affected by dietary fatty acid perturbation in this study. Taken together, these data indicate that fractional catabolic rate is the predominant mechanism by which dietary fatty acids differentially modulate circulating concentrations of HDL apo A-I in this species when all other dietary variables are held constant.

Dietary monounsaturated and polyunsaturated fatty acids are comparable in their effects on hepatic apolipoprotein mRNA abundance and liver lipid concentrations when substituted for saturated fatty acids in cynomolgus monkeys.

Although studies have shown that saturated and polyunsaturated fats can mediate plasma lipid and apolipoprotein (apo) concentrations at the mRNA level, there is little data on the role of monounsaturated fats. We determined hepatic lipid and apo mRNA levels in 10 cynomolgus monkeys fed three diets that provided 30% of energy as fat with 0.1% cholesterol by weight and differed solely by the substitution of saturated, mono- and polyunsaturated fats as 60% of total fat energy. Total, LDL, and HDL cholesterol, as well as LDL apo B, HDL apo A-I and HDL total apo C concentrations, were reduced with the mono- and polyunsaturated fat diets relative to the saturated fat diet. Although fat saturation did not significantly affect hepatic apo A-I, B, C-II, or E mRNA abundance, hepatic apo C-III mRNA concentrations were uniformly lower (-23%, P < 0.01) with the mono- and polyunsaturated fat diets than with the saturated fat diet. Interestingly, liver triglycerides were significantly elevated with the monounsaturated fat diet relative to the saturated fat diet, but no other differences in hepatic lipids were noted among diets. Hepatic triglyceride composition was shown to reflect dietary fatty acid composition, with liver triglycerides enriched in myristic and palmitic fatty acids during the saturated fat diet, oleic acid during the monounsaturated fat diet and linoleic acid during the polyunsaturated fat diet. We conclude that dietary monounsaturated fats are comparable to polyunsaturated fats in their effects on hepatic lipid and apo mRNA levels in this species, with both unsaturated fats significantly reducing only hepatic apo C-III mRNA abundance relative to saturated fat.

Determinants of plasma vitamins and lipids: the Working Well Study.

This study was conducted to assess the determinants of plasma concentrations of alpha-tocopherol, beta-carotene, retinol, and cholesterol fractions in a randomly selected subset of 203 workers participating in a worksite-based health intervention trial. Workers were from four companies in eastern and central Massachusetts, and all completed an 84-item semiquantitative food frequency questionnaire as part of baseline (preintervention) self-assessment instruments. At the time of fasting blood sampling, each participant also completed a short screening questionnaire for assessment of changes in dietary habits and tobacco exposure and for collection of data on use of vitamins and nutritional supplements. On the basis of the self-reported data, the authors found that they could explain 35% of the variability in plasma beta-carotene, 73% of the variability in alpha-tocopherol, 36% of the variability in retinol, and 19% of the variability in cholesterol. Plasma beta-carotene levels appeared to be affected by the use of supplements that did not contain carotene, indicating a beta-carotene sparing capability of other agents contained in these preparations. Plasma alpha-tocopherol levels were not similarly affected. These results compare favorably with those from studies that used more intensive dietary assessment techniques as the comparison criterion. Results are discussed in terms of implications for use of self-reported data in epidemiologic study analyses.

Rice bran oil consumption and plasma lipid levels in moderately hypercholesterolemic humans.

The effect of rice bran oil, and oil not commonly consumed in the United States, on plasma lipid and apolipoprotein concentrations was studied within the context of a National Cholesterol Education Panel (NCEP) Step 2 diet and compared with the effects of canola, corn, and olive oils. The study subjects were 15 middle-aged and elderly subjects (8 postmenopausal women and 7 men; age range, 44 to 78 years) with elevated low-density lipoprotein (LDL) cholesterol (C) concentrations (range, 133 to 219 mg/dL). Diets enriched in each of the test oils were consumed by each subject for 32-day periods in a double-blind fashion and were ordered in a Latin square design. All food and drink were provided by the metabolic research unit. Diet components were identical (17% of calories as protein, 53% as carbohydrate, 30% as fat [< 7% as saturated fat], and 80 mg cholesterol/1000 kcal) except that two thirds of the fat in each diet was contributed by rice bran, canola, corn, or olive oil. Mean +/- SD plasma total cholesterol concentrations were 192 +/- 19, 194 +/- 20, 194 +/- 19, and 205 +/- 19 mg/dL, and LDL-C concentrations were 109 +/- 30, 109 +/- 26, 108 +/- 31, and 112 +/- 29 mg/dL after consumption of the rice bran, canola, corn, and olive oil-enriched diets, respectively. Plasma cholesterol and LDL-C concentrations were similar and statistically indistinguishable when the subjects consumed the rice bran, canola, and corn oil-enriched diets and lower than when they consumed the olive oil-enriched diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of dietary fat saturation on plasma lipoprotein(a) and hepatic apolipoprotein(a) mRNA concentrations in cynomolgus monkeys.

Plasma lipoprotein(a) (Lp(a)) concentration is an independent risk factor for the development of premature coronary artery disease. Although the majority of available data indicates that circulating Lp(a) levels are under strict genetic regulation, there is some evidence that this parameter may be subject to dietary modification as well. The effects of dietary fat saturation on plasma Lp(a) levels and hepatic apolipoprotein(a) (apo(a)) mRNA abundance were examined in ten unrelated cynomolgus monkeys which were fed each of three experimental diets enriched in saturated (SAT), monounsaturated (MONO), or polyunsaturated (POLY) fatty acids in a crossover design consisting of three 13-week periods. Each diet contained 30% of calories as fat with 0.1% dietary cholesterol by weight and differed solely by the isocaloric substitution of fatty acids as 60% of total fat calories. The mean Lp(a) level for these animals during the SAT diet (13.4 +/- 2.4 mg/dl) was significantly greater as compared with those observed during the MONO (8.6 +/- 2.2 mg/dl, P < 0.0003) and POLY (9.3 +/- 2.1 mg/dl, P < 0.002) diets, while the difference noted between the MONO and POLY diets was nonsignificant. Hepatic apo(a) mRNA abundance was decreased in these animals during the MONO diet relative to both the SAT and POLY diets, with only the difference between the SAT and MONO diets achieving statistical significance (P < 0.02). Our data demonstrate that the substitution of dietary SATs with either MONOs or POLYs result in significant reductions of Lp(a) levels in these monkeys. However, only the MONO diet significantly decreased hepatic apo(a) mRNA levels relative to the SAT diet, suggesting that dietary MONOs and POLYs may differ in the manner by which they regulate plasma Lp(a) levels.

A diet enriched in monounsaturated fats decreases low density lipoprotein concentrations in cynomolgus monkeys by a different mechanism than does a diet enriched in polyunsaturated fats.

To determine the mechanisms whereby dietary fat saturation influences LDL cholesterol and apolipoprotein B concentrations, 10 cynomolgus monkeys were fed each of three experimental diets enriched in saturated, monounsaturated or polyunsaturated fatty acids in a crossover design consisting of three 13-wk periods. Each diet contained 30% of energy as fat with 0.05 mg cholesterol/kJ and differed solely by the isocaloric substitution of fatty acids as 60% of total fat energy. The replacement of dietary saturated fatty acids with either mono- or polyunsaturated fatty acids resulted in significant reductions of plasma total cholesterol (-17% and -30%, respectively), HDL cholesterol (-32% and -41%, respectively), apoA-1 (-37% and -44%, respectively), and apolipoprotein B (-28% and -36%, respectively) concentrations. Additionally, when dietary polyunsaturated fatty acids were substituted for saturated fatty acids, a 27% reduction in VLDL + LDL cholesterol was significant. Metabolic experiments suggested that the significantly reduced concentrations of apolipoprotein B observed during the monounsaturated and polyunsaturated fatty acid phases relative to the saturated fatty acid phase could not be entirely explained by changes in LDL apolipoprotein B clearance but rather were likely due to decreased LDL apolipoprotein B production rates. However, enhanced LDL apolipoprotein B catabolism accounted for the even greater reductions in VLDL + LDL cholesterol and apolipoprotein B concentrations observed during the polyunsaturated fatty acid phase vs. the monounsaturated fatty acid phase. Our data suggest that monounsaturated and polyunsaturated fatty acids lower apolipoprotein B concentrations by distinct mechanisms, with polyunsaturated fatty acids affecting LDL apolipoprotein B catabolism as well as production.

Effects of dietary fats and cholesterol on liver lipid content and hepatic apolipoprotein A-I, B, and E and LDL receptor mRNA levels in cebus monkeys.

The effects of the long-term administration of the dietary fats coconut oil and corn oil at 31% of calories with or without 0.1% (wt/wt) dietary cholesterol on plasma lipoproteins, apolipoproteins (apo), hepatic lipid content, and hepatic apoA-I, apoB, apoE, and low density lipoprotein (LDL) receptor mRNA abundance were examined in 27 cebus monkeys. Relative to the corn oil-fed animals, no significant differences were noted in any of the parameters of the corn oil plus cholesterol-fed group. In animals fed coconut oil without cholesterol, significantly higher (P less than 0.05) plasma total cholesterol (145%), very low density lipoprotein (VLDL) + LDL (201%) and high density lipoprotein (HDL) (123%) cholesterol, apoA-I (103%), apoB (61%), and liver cholesteryl ester (263%) and triglyceride (325%) levels were noted, with no significant differences in mRNA levels relative to the corn oil only group. In animals fed coconut oil plus cholesterol, all plasma parameters were significantly higher (P less than 0.05), as were hepatic triglyceride (563%) and liver apoA-I (123%) and apoB (87%) mRNA levels relative to the corn oil only group, while hepatic LDL receptor mRNA (-29%) levels were significantly lower (P less than 0.05). Correlation coefficient analyses performed on pooled data demonstrated that liver triglyceride content was positively associated (P less than 0.05) with liver apoA-I and apoB mRNA levels and negatively associated (P less than 0.01) with hepatic LDL receptor mRNA levels. Liver free and esterified cholesterol levels were positively correlated (P less than 0.05) with liver apoE mRNA levels and negatively correlated (P less than 0.025) with liver LDL receptor mRNA levels. Interestingly, while a significant correlation (P less than 0.01) was noted between hepatic apoA-I mRNA abundance and plasma apoA-I levels, no such relationship was observed between liver apoB mRNA and plasma apoB levels, suggesting that the hepatic mRNA of apoA-I, but not that of apoB, is a major determinant of the circulating levels of the respective apolipoprotein. Our data indicate that a diet high in saturated fat and cholesterol may increase the accumulation of triglyceride and cholesterol in the liver, each resulting in the suppression of hepatic LDL receptor mRNA levels. We hypothesize that such elevations in hepatic lipid content differentially alter hepatic apoprotein mRNA levels, with triglyceride increasing hepatic mRNA concentrations for apoA-I and B and cholesterol elevating hepatic apoE mRNA abundance.

Effect of corn and coconut oil-containing diets with and without cholesterol on high density lipoprotein apoprotein A-I metabolism and hepatic apoprotein A-I mRNA levels in cebus monkeys.

The mechanism(s) by which diets containing corn or coconut oil (31% of energy as fat) totally free of cholesterol or with 0.1% added cholesterol by weight (0.3 mg/kcal) affect plasma high density lipoprotein cholesterol (HDL-C), apoprotein (apo) A-I levels, apo A-I kinetics, and hepatic apo A-I mRNA concentrations were investigated in 26 cebus monkeys. Coconut oil-fed monkeys had elevated levels of plasma total cholesterol (217%), very low density lipoprotein plus low density lipoprotein cholesterol (331%), HDL-C (159%), and apo A-I (117%) compared with corn oil-fed animals. Although the addition of cholesterol to the corn oil diet significantly increased these parameters, no such effects were seen when cholesterol was added to the coconut-oil diet. Both the type of fat and cholesterol in the diet significantly affected HDL apo A-I metabolism by decreasing apo A-I fractional catabolic rate and increasing apo A-I production rate in the coconut oil-fed groups. The decrease in apo A-I fractional catabolic rate in the coconut oil-fed animals was also associated with an increase in the HDL core lipid to surface ratio. Liver apo A-I mRNA abundance was elevated in the coconut oil-fed groups; however, dietary cholesterol had no affect on these levels. The lack of parallel effects of dietary fat and cholesterol on apo A-I production rate and liver apo A-I mRNA levels suggests that the increase in the apo A-I production rate observed in the coconut oil-fed groups resulted from the fat-induced rise in liver apo A-I mRNA abundance, whereas the cholesterol-induced rise in the apo A-I production rate resulted from a mechanism other than changes in liver apo A-I mRNA levels.

Rice bran oil lowers serum total and low density lipoprotein cholesterol and apo B levels in nonhuman primates.

The hypolipidemic response of rice bran oil (RBO) was investigated in nonhuman primates fed semi-purified diets containing blends of oils which included RBO at 0-35% Kcals as dietary fat. The studies demonstrated the following: (a) the degree of reduction of serum total cholesterol (TC) and low density lipoprotein cholesterol (LDLC) was highly correlated with initial serum cholesterol levels of the monkey on the stabilization diet; (b) the content of rice bran oil in the diet was the predominant factor influencing serum TC, LDLC and apoB causing up to a 40% reduction in LDLC without affecting high density lipoprotein cholesterol (HDLC) when RBO was the sole dietary oil fed; (c) the cholesterol-lowering capabilities of RBO were not explained by its fatty acid composition. These studies suggest that RBO may be an additional vegetable oil which lowers serum cholesterol levels by unique mechanisms which will require further study.

Effect of dietary fat saturation and cholesterol on LDL composition and metabolism. In vivo studies of receptor and nonreceptor-mediated catabolism of LDL in cebus monkeys.

The mechanism(s) by which polyunsaturated fats reduce low density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B were investigated in 20 cebus monkeys (Cebus albifrons) fed diets containing corn oil or coconut oil as fat (31% of calories) with or without dietary cholesterol (0.1% by weight) for 3 to 10 years. Coconut-oil feeding compared to corn-oil feeding resulted in significant increases in levels of plasma total cholesterol (176%), very low density lipoprotein (VLDL)-LDL cholesterol (236%), high density lipoprotein (HDL) cholesterol (148%), apo B (78%), and apo A-I (112%). The addition of dietary cholesterol to corn oil compared to corn oil alone resulted in smaller, but significant, increases in levels of total cholesterol (44%), HDL cholesterol (40%), and apo A-I (33%). Although the increases in VLDL-LDL cholesterol were of similar magnitude (52%), they barely failed to reach statistical significance (p less than 0.08), while the changes in apo B levels were negligible. The addition of dietary cholesterol to coconut oil, compared to coconut oil alone, resulted in no significant changes in lipoprotein cholesterol or apoproteins, although levels of VLDL-LDL cholesterol and apo B values increased 22% and 16%, respectively. Although hepatic free cholesterol content was not altered by diet, coconut-oil compared to corn-oil feeding resulted in significant increases in hepatic cholesteryl esters (236%) and triglycerides (325%), the latter increasing still further when dietary cholesterol was added to coconut oil (563%). To further assess the effects of these dietary changes on LDL metabolism, radioiodinated normal and glucosylated LDL kinetics were performed. The production rate of LDL apo B was not altered by diet. With corn-oil feeding, 63% of LDL catabolism was via the receptor-mediated pathway. Coconut-oil compared to corn-oil feeding resulted in a 50% decrease in receptor-mediated LDL apo B fractional catabolic rate (FCR) and a 27% reduction in nonreceptor-mediated LDL apo B FCR. The addition of dietary cholesterol to corn oil, compared to corn oil alone, resulted in no significant effect on LDL apo B catabolism. The addition of dietary cholesterol to coconut oil, compared to coconut oil alone, was associated with no significant change in nonreceptor catabolism of LDL apo B but with a 58% decrease in receptor-mediated catabolism of LDL (p less than 0.059). The diet-induced alterations of LDL catabolism were significantly correlated with hepatic lipids, which were enriched in saturated fatty acids.(ABSTRACT TRUNCATED AT 400 WORDS)