Dietary lycopene attenuates cigarette smoke-promoted nonalcoholic steatohepatitis by preventing suppression of antioxidant enzymes in ferrets.

Cigarette smoke (CS) is an independent risk factor in development of nonalcoholic steatohepatitis (NASH) and fibrosis. Lycopene, a carotenoid naturally occurring in tomatoes, has been shown to be a protective agent against tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced NASH. In the present study using a ferret model we investigated whether CS promotes NASH and whether dietary lycopene can inhibit CS-promoted NASH development, and if so, what potential mechanisms were involved. Ferrets were divided into 4 groups (n=12-16/group): control, NNK/CS exposed, NNK/CS plus low-dose lycopene (2.2 mg/kg BW/day), and NNK/CS plus high-dose lycopene (6.6 mg/kg BW/day) groups, for 26 weeks. Results showed that hepatic steatosis, infiltrates of inflammatory cells, and the number and size of inflammatory foci in liver, together with key genes involved in hepatic fibrogenesis were higher in the NNK/CS group compared to the control group; a lycopene diet reversed these changes to the levels of the control group. Interestingly, a major lycopene cleavage enzyme, beta-carotene 9',10'-oxygenase (BCO2), which recently has been recognized to play metabolic roles beyond cleavage function, was down-regulated by NNK/CS exposure, but this decrease was prevented by lycopene feeding. NNK/CS exposure also downregulated liver expression of antioxidant enzymes and upregulated oxidative stress marker, which were all prevented by lycopene. In conclusion, our results suggest that CS can promote development of NASH and liver fibrosis in ferrets, which is associated with downregulation of BCO2 and impairment of antioxidant system in liver; dietary lycopene may inhibit CS-promoted NASH by preventing suppression of BCO2 and decline in antioxidant network.

Xanthophyll ß-Cryptoxanthin Inhibits Highly Refined Carbohydrate Diet-Promoted Hepatocellular Carcinoma Progression in Mice.

SCOPE: ß-Cryptoxanthin (BCX) can be cleaved by both ß-carotene 15,15'-oxygenase (BCO1) and ß-carotene 9',10'-oxygenase (BCO2), generating biological active vitamin A and apocarotenoids. We examined whether BCX feeding could inhibit diethylnitrosamine (DEN)-initiated, highly refined carbohydrate diet (HRCD)-promoted hepatocellular carcinoma (HCC) development, dependent or independent of BCO1/BCO2 activity. METHODS AND RESULTS: Two-week-old male wild-type (WT) and BCO1-/- /BCO2-/- double knockout (DKO) mice are given a single intraperitoneal injection of DEN (25 mg kg-1 body weight) to initiate hepatic carcinogenesis. At 6 weeks of age, all animals are fed HRCD (66.5% of energy from carbohydrate) with or without BCX for 24 weeks. BCX feeding increases hepatic vitamin A levels in WT mice, but not in DKO mice that shows a significant accumulation of hepatic BCX. Compared to their respective HRCD littermates, both WT and DKO fed BCX have significantly lower HCC multiplicity, average tumor size, and total tumor volume, and the steatosis scores. The chemopreventive effects of BCX are associated with increased p53 protein acetylation and decreased protein levels of lactate dehydrogenase and hypoxia-inducible factor-1α in tumors. CONCLUSION: This study suggests that BCX feeding may alleviate HRCD-promoted HCC progression by modulating the acetylation of p53, hypoxic tumor microenvironment, and glucose metabolism, independent of BCO1/BCO2.

Dietary tomato powder inhibits alcohol-induced hepatic injury by suppressing cytochrome p450 2E1 induction in rodent models.

Chronic and excessive alcohol consumption leads to the development of alcoholic liver disease (ALD) and greatly increases the risk of liver cancer. Induction of the cytochrome p450 2E1 (CYP2E1) enzyme by chronic and excessive alcohol intake is known to play a role in the pathogenesis of ALD. High intake of tomatoes, rich in the carotenoid lycopene, is associated with a decreased risk of chronic disease. We investigated the effects of whole tomato (tomato powder, TP), partial tomato (tomato extract, TE), and purified lycopene (LYC) against ALD development in rats. Of the three supplements, only TP reduced the severity of alcohol-induced steatosis, hepatic inflammatory foci, and CYP2E1 protein levels. TE had no effect on these outcomes and LYC greatly increased inflammatory foci in alcohol-fed rats. To further support the protective effect of TP against ALD, TP was supplemented in a carcinogen (diethylnitrosamine, DEN)-initiated alcohol-promoted mouse model. In addition to reduced steatosis and inflammatory foci, TP abolished the presence of preneoplastic foci of altered hepatocytes in DEN-injected mice fed alcohol. These reductions were associated with decreased hepatic CYP2E1 protein levels, restored levels of peroxisome proliferator-activated receptor-α and downstream gene expression, decreased inflammatory gene expression, and reduced endoplasmic reticulum stress markers. These data provide strong evidence for TP as an effective whole food prevention strategy against ALD.

Lycopene attenuated hepatic tumorigenesis via differential mechanisms depending on carotenoid cleavage enzyme in mice.

Obesity is associated with increased liver cancer risks and mortality. We recently showed that apo-10'-lycopenoic acid, a lycopene metabolite generated by beta-carotene-9',10'-oxygenase (BCO2), inhibited carcinogen-initiated, high-fat diet (HFD)-promoted liver inflammation, and hepatic tumorigenesis development. The present investigation examined the outstanding question of whether lycopene could suppress HFD-promoted hepatocellular carcinoma (HCC) progression, and if BCO2 expression is important using BCO2-knockout (BCO2-KO) and wild-type male mice. Results showed that lycopene supplementation (100 mg/kg diet) for 24 weeks resulted in comparable accumulation of hepatic lycopene (19.4 vs. 18.2 nmol/g) and had similar effects on suppressing HFD-promoted HCC incidence (19% vs. 20%) and multiplicity (58% vs. 62%) in wild-type and BCO2-KO mice, respectively. Intriguingly, lycopene chemopreventive effects in wild-type mice were associated with reduced hepatic proinflammatory signaling (phosphorylation of NK-κB p65 and STAT3; IL6 protein) and inflammatory foci. In contrast, the protective effects of lycopene in BCO2-KO but not in wild-type mice were associated with reduced hepatic endoplasmic reticulum stress-mediated unfolded protein response (ER(UPR)), through decreasing ER(UPR)-mediated protein kinase RNA-activated like kinase-eukaryotic initiation factor 2α activation, and inositol requiring 1α-X-box-binding protein 1 signaling. Lycopene supplementation in BCO2-KO mice suppressed oncogenic signals, including Met mRNA, ß-catenin protein, and mTOR complex 1 activation, which was associated with increased hepatic microRNA (miR)-199a/b and miR214 levels. These results provided novel experimental evidence that dietary lycopene can prevent HFD-promoted HCC incidence and multiplicity in mice, and may elicit different mechanisms depending on BCO2 expression.

Lycopene metabolite, apo-10'-lycopenoic acid, inhibits diethylnitrosamine-initiated, high fat diet-promoted hepatic inflammation and tumorigenesis in mice.

Obesity is associated with increased risk in hepatocellular carcinoma (HCC) development and mortality. An important disease control strategy is the prevention of obesity-related hepatic inflammation and tumorigenesis by dietary means. Here, we report that apo-10'-lycopenoic acid (APO10LA), a cleavage metabolite of lycopene at its 9',10'-double bond by carotene-9',10'-oxygenase, functions as an effective chemopreventative agent against hepatic tumorigenesis and inflammation. APO10LA treatment on human liver THLE-2 and HuH7 cells dose dependently inhibited cell growth and upregulated sirtuin 1 (SIRT1), a NAD(+)-dependent protein deacetylase that may suppress hepatic carcinogenesis. This observed SIRT1 induction was associated with decreased cyclin D1 protein, increased cyclin-dependent kinase inhibitor p21 protein expression, and induced apoptosis. APO10LA supplementation (10 mg/kg diet) for 24 weeks significantly reduced diethylnitrosamine-initiated, high fat diet (HFD)-promoted hepatic tumorigenesis (50% reduction in tumor multiplicity; 65% in volume) and lung tumor incidence (85% reduction) in C57Bl/6J mice. The chemopreventative effects of APO10LA were associated with increased hepatic SIRT1 protein and deacetylation of SIRT1 targets, as well as with decreased caspase-1 activation and SIRT1 protein cleavage. APO10LA supplementation in diet improved glucose intolerance and reduced hepatic inflammation [decreased inflammatory foci, TNFα, interleukin (IL)-6, NF-κB p65 protein expression, and STAT3 activation] in HFD-fed mice. Furthermore, APO10LA suppressed Akt activation, cyclin D1 gene, and protein expression and promoted PARP protein cleavage in transformed cells within liver tumors. Taken together, these data indicate that APO10LA can effectively inhibit HFD-promoted hepatic tumorigenesis by stimulating SIRT1 signaling while reducing hepatic inflammation.

ß-cryptoxanthin restores nicotine-reduced lung SIRT1 to normal levels and inhibits nicotine-promoted lung tumorigenesis and emphysema in A/J mice.

Nicotine, a large constituent of cigarette smoke, is associated with an increased risk of lung cancer, but the data supporting this relationship are inconsistent. Here, we found that nicotine treatment not only induced emphysema but also increased both lung tumor multiplicity and volume in 4-nitrosamino-1-(3-pyridyl)-1-butanone (NNK)-initiated lung cancer in A/J mice. This tumor-promoting effect of nicotine was accompanied by significant reductions in survival probability and lung Sirtuin 1 (SIRT1) expression, which has been proposed as a tumor suppressor. The decreased level of SIRT1 was associated with increased levels of AKT phosphorylation and interleukin (il)-6 mRNA but decreased tumor suppressor p53 and retinoic acid receptor (RAR)-ß mRNA levels in the lungs. Using this mouse model, we then determined whether ß-cryptoxanthin (BCX), a xanthophyll that is strongly associated with a reduced risk of lung cancer in several cohort studies, can inhibit nicotine-induced emphysema and lung tumorigenesis. We found that BCX supplementation at two different doses was associated with reductions of the nicotine-promoted lung tumor multiplicity and volume, as well as emphysema in mice treated with both NNK and nicotine. Moreover, BCX supplementation restored the nicotine-suppressed expression of lung SIRT1, p53, and RAR-ß to that of the control group, increased survival probability, and decreased the levels of lung il-6 mRNA and phosphorylation of AKT. The present study indicates that BCX is a preventive agent against emphysema and lung cancer with SIRT1 as a potential target. In addition, our study establishes a relevant animal lung cancer model for studying tumor growth within emphysematous microenvironments.

Novel soybean oils differing in fatty acid composition alter immune functions of moderately hypercholesterolemic older adults.

Linoleic acid (LA) and α-linolenic acid (ALA) are essential fatty acids that play an important role in modulation of T cell proliferation. The effects of consuming novel soybean oils varying in LA:ALA ratios on T cell proliferation and inflammatory responses were assessed in older adults. Eighteen participants (>50 y old) with elevated cholesterol concentrations (3.37-4.14 mmol/L LDL cholesterol) consumed 5 experimental diets in random order for periods of 35 d. Each diet contained 30% of energy as fat, two-thirds of which was high-oleic acid soybean oil (HiOleic-SO), soybean oil (SO), low-SFA soybean oil (LoSFA-SO), hydrogenated soybean oil (Hydrog-SO), or low-ALA soybean oil (LoALA-SO), resulting in LA:ALA ratios of 2.98, 8.70, 9.69, 15.2, and 18.3, respectively. Participants had higher proliferative responses to phytohemagglutinin (PHA) compared with baseline following consumption of SO (26%; P < 0.05), LoSFA-SO (22%; P < 0.05), or HiOleic-SO (24%; P < 0.05) diets. Proliferative response was similar to the baseline after participants consumed diets with an LA:ALA ratio >10 (Hydrog-SO and LoALA-SO). Post-diet intervention, LA:ALA ratios correlated with proliferative responses to PHA (r = -0.87; P = 0.05). An optimal proliferative response was observed at an LA:ALA ratio of 8.70, with an inverse correlation between proliferative response and LA:ALA ratios >8.70. These effects were independent of changes in the production of PGE(2), inflammatory cytokines, or cytokines involved in growth of lymphocytes. These data suggest that the LA:ALA ratio modulates the proliferative ability of T lymphocytes, which may be due to subtle changes in fatty acid composition of the phospholipids in immune cells.

Cost implications of alternative sources of (n-3) fatty acid consumption in the United States.

The Dietary Guidelines for Americans 2010 provides authoritative advice on what Americans should eat to stay healthy. These guidelines provide a quantitative recommendation to consume 250 mg/d of (n-3) fatty acids (also known as omega-3 fatty acids). To achieve this goal, Americans would need to more than triple the amount of EPA and DHA currently consumed. This paper assessed the cost implications of increased levels of EPA and DHA from marine and nonmarine food sources using data from the 2007-2008 NHANES, USDA nutrient data base, and the USDA Center for the Nutrition Policy and Promotion food price data. Stearidonic acid (SDA)-enhanced soybean oil is a lower cost alternative to commonly consumed marine food as a source of EPA. In addition, given that SDA-enhanced soybean oil is intended to be used as an ingredient in a variety of products, this may enable consumers to increase consumption of EPA through commonly consumed foods.

Dietary lycopene and tomato extract supplementations inhibit nonalcoholic steatohepatitis-promoted hepatocarcinogenesis in rats.

Epidemiological and experimental studies provide supportive evidence that lycopene (LY), a major carotenoid from tomatoes and tomato products, may act as a chemopreventive agent against certain types of cancers. We recently showed that high-fat diet (HFD)-induced nonalcoholic steatohepatitis (NASH) promoted diethylnitrosamine (DEN)-initiated hepatocarcinogenesis in a rat model. Using this model, we investigated the efficacy of an equivalent dosage of dietary LY from either a pure compound or a tomato extract (TE) against NASH-promoted hepatocarcinogenesis. Six groups of rats were injected with DEN and then fed either Lieber-DeCarli control diet or HFD with or without LY or TE for 6 weeks. Results showed that both LY and TE supplementations significantly decreased the number of altered hepatic foci expressing the placental form of glutathione S-transferase in the livers of HFD-fed rats. This was associated with significantly lower proliferating cell nuclear antigen positive hepatocytes and cyclinD1 protein, as well as decreased activation of extracellular signal-regulated kinase and nuclear NF-kappaB. Although both LY and TE supplementations reduced HFD-induced lipid peroxidation in the livers, we observed significantly decreased cytochrome P450 2E1, inflammatory foci and mRNA expression of proinflammatory cytokines (TNF-alpha, IL-1beta and IL-12) in the HFD+TE fed group but increased nuclear NF-E2-related factor-2 and heme oxygenase-1 proteins in the HFD+LY fed group, relative to HFD feeding alone. These data indicate that LY and TE can inhibit NASH-promoted hepatocarcinogenesis mainly as a result of reduced oxidative stress, which could be fulfilled through different mechanisms.

Substitution of vegetable oil for a partially-hydrogenated fat favorably alters cardiovascular disease risk factors in moderately hypercholesterolemic postmenopausal women.

OBJECTIVE: Compared to vegetable oils in their unmodified state, partially-hydrogenated fat is associated with less favorable effects on cardiovascular disease (CVD) risk factors. Acceptable alternatives must be adjudicated. Our objective was to assess the effect of a recent commercial fat substitution, corn oil for partially-hydrogenated soybean oil. METHODS: Using a double-blind cross-over design, 30 postmenopausal women >or=50 years with LDL-cholesterol concentrations >or=120 mg/dL were randomly assigned to each of two 35-day phases; all food and beverage was provided to maintain body weight. Corn or partially-hydrogenated soybean oil was incorporated throughout the diet and contributed two-thirds of fat. Primary outcomes included fasting and non-fasting lipid, lipoprotein, apolipoprotein, and fasting high sensitivity C-reactive protein (hsCRP) concentrations; secondary outcomes included fasting small dense LDL (sdLDL)-cholesterol, remnant lipoprotein cholesterol (RemLC), glycated albumin, adiponectin and immunoreactive insulin concentrations, and endogenous cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyl transferase (LCAT) activities. RESULTS: Relative to the partially-hydrogenated soybean oil enriched diet, the corn oil enriched diet resulted in lower fasting total cholesterol (7%; P<0.0001), LDL-cholesterol (10%; P<0.0001), VLDL-cholesterol (7%; P=0.052), apo B (9%; P<0.0001), lipoprotein (a) [Lp(a)] (5%; P=0.024), sdLDL-cholesterol (17%; P=0.001), and RemLC (20%; P=0.007) concentrations, and no significant effect on the other outcomes. Changes in postprandial (4-h post-meal) lipid, lipoprotein and apolipoprotein concentrations were similar to the fasting state. CONCLUSION: The replacement of partially-hydrogenated soybean oil with corn oil favorably affects a range of CVD risk factors and is an appropriate option to decrease cardiovascular disease risk factors in moderately hypercholesterolemic individuals.

High dose lycopene supplementation increases hepatic cytochrome P4502E1 protein and inflammation in alcohol-fed rats.

Recent in vitro evidence suggests that the antioxidant lycopene can prevent alcohol-induced oxidative stress and inflammation. However, knowledge of possible interactions in vivo between escalating doses of lycopene and chronic alcohol ingestion are lacking. In this study, we investigated potential interactions between alcohol ingestion and lycopene supplementation and their effect on hepatic lycopene concentration, cytochrome P4502E1 (CYP2E1) induction, and inflammation. Fischer 344 rats (6 groups, n = 10 per group) were fed either a liquid ethanol Lieber-DeCarli diet or a control diet (isocaloric maltodextrin substituted for ethanol) with or without lycopene supplementation at 2 doses (1.1 or 3.3 mg x kg body weight(-1) x d(-1)) for 11 wk. Plasma and hepatic concentrations of lycopene isomers were assessed by HPLC analysis. We examined expressions of hepatic CYP2E1 and tumor necrosis factor-alpha (TNFalpha) and the incidence of hepatic inflammatory foci. Both plasma and hepatic lycopene concentrations were greater in alcohol-fed rats than in control rats supplemented with identical doses of lycopene. In contrast, alcohol-fed rats had a lower percentage of lycopene cis isomers in the plasma and the liver compared with control rats fed the same dose of lycopene. Notably, lycopene supplementation at the higher dose significantly induced hepatic CYP2E1 protein, TNFalpha mRNA, and the incidence of inflammatory foci in the alcohol-fed rats but not in the control rats. These data indicate an interaction between chronic alcohol ingestion and lycopene supplementation and suggest a need for caution among individuals consuming high amounts of both alcohol and lycopene.

Effect of soy protein from differently processed products on cardiovascular disease risk factors and vascular endothelial function in hypercholesterolemic subjects.

BACKGROUND: The magnitude of the effect of soy protein on lipoprotein concentrations is variable. This discordance is likely attributable to the various forms of soy protein used and to unrecognized shifts in dietary fatty acid, cholesterol, and fiber. OBJECTIVE: The objective was to evaluate the effect of soybean processing as well as soy consumption relative to animal protein, independent of alterations in major dietary variables, on cardiovascular disease risk factors and vascular endothelial function. DESIGN: Twenty-eight hypercholesterolemic subjects (LDL cholesterol >/=3.36 mmol/L) aged >50 y consumed each of 4 diets for 6-wk periods according to a randomized crossover design. The diets [55% of energy as carbohydrate, 30% of energy as fat, and 15% of energy as protein-7.5% of energy as experimental protein (37.5 g/d)] were designed to contain products made from either whole soybeans, soyflour, or soymilk and were compared with a diet containing an equivalent amount of animal protein (meat, chicken, and dairy products). The cholesterol, fiber, and fatty acid profiles of the diets were equalized. All food and drink were provided, and body weight was maintained throughout the study. RESULTS: No significant differences in blood pressure, vascular endothelial function, or total cholesterol, VLDL-cholesterol, triacylglycerol, apolipoprotein B, or C-reactive protein concentrations were observed between the diets. Consumption of the soymilk diet resulted in a modest decrease (4%) in LDL-cholesterol concentrations compared with the animal-protein and soyflour diets (P < 0.05) and higher HDL-cholesterol (1%) and apolipoprotein A-I (2%) concentrations compared with the soybean and soyflour diets (P < 0.05). CONCLUSIONS: The results suggest that the consumption of differently processed soy-based products and different types of protein (animal and soy) has little clinical effect on cardiovascular disease risk factors, including peripheral endothelial function, when other major dietary variables are held constant.

Novel soybean oils with different fatty acid profiles alter cardiovascular disease risk factors in moderately hyperlipidemic subjects.

BACKGROUND: A variety of soybean oils were developed with improved oxidative stability and functional characteristics for use as alternatives to partially hydrogenated fat. OBJECTIVE: The objective was to assess the effect of selectively bred and genetically modified soybean oils with altered fatty acid profiles, relative to common soybean and partially hydrogenated soybean oils, on cardiovascular disease risk factors. DESIGN: Thirty subjects (16 women and 14 men) aged >50 y with LDL-cholesterol concentrations >130 mg/dL at screening consumed 5 experimental diets in random order for 35 d each. Diets contained the same foods and provided 30% of energy as fat, of which two-thirds was either soybean oil (SO), low-saturated fatty acid soybean oil (LoSFA-SO), high-oleic acid soybean oil (HiOleic-SO), low-alpha-linolenic acid soybean oil (LoALA-SO), or partially hydrogenated soybean oil (Hydrog-SO). RESULTS: Plasma phospholipid patterns reflected the predominant fat in the diet. LDL-cholesterol concentrations were 3.66 +/- 0.67(b), 3.53 +/- 0.77(b), 3.70 +/- 0.66(b), 3.71 +/- 0.64(a,b), and 3.92 +/- 0.70(a) mol/L; HDL-cholesterol concentrations were 1.32 +/- 0.32(a,b), 1.32 +/- 0.35(b), 1.36 +/- 0.33(a), 1.32 +/- 0.33(b), and 1.32 +/- 0.32(a,b) mol/L for the SO, LoSFA-SO, HiOleic-SO, LoALA-SO, and Hydrog-SO diets, respectively (values with different superscript letters are significantly different, P < 0.05). No significant effects were observed on VLDL-cholesterol, triacylglycerol, lipoprotein(a), and C-reactive protein concentrations or on ratios of LDL cholesterol to apolipoprotein B (apo B) and HDL cholesterol to apo A-I. Total cholesterol:HDL cholesterol was lower after subjects consumed the unhydrogenated soybean oils than after they consumed the Hydrog-SO diet. CONCLUSIONS: All varieties of soybean oils resulted in more favorable lipoprotein profiles than did the partially hydrogenated form. These soybean oils may provide a viable option for reformulation of products to reduce the content of trans fatty acids.

Palm and partially hydrogenated soybean oils adversely alter lipoprotein profiles compared with soybean and canola oils in moderately hyperlipidemic subjects.

BACKGROUND: Partially hydrogenated fat has an unfavorable effect on cardiovascular disease risk. Palm oil is a potential substitute because of favorable physical characteristics. OBJECTIVE: We assessed the effect of palm oil on lipoprotein profiles compared with the effects of both partially hydrogenated fat and oils high in monounsaturated or polyunsaturated fatty acids. DESIGN: Fifteen volunteers aged > or =50 y with LDL cholesterol > or =130 mg/dL were provided with food for each of 4 diets (35 d/phase) varying in type of fat (partially hydrogenated soybean, soybean, palm, or canola; two-thirds fat, 20% of energy). Plasma fatty acid profiles, lipids, lipoproteins, apolipoprotein A-I, apolipoprotein B, lipoprotein(a), glucose, insulin, HDL subfractions, and indicators of lipoprotein metabolism (HDL-cholesterol fractional esterification rate, cholesteryl ester transfer protein, phospholipid transfer protein, and paraoxonase activities) were measured at the end of each phase. RESULTS: Plasma fatty acid profiles reflected the main source of dietary fat. Partially hydrogenated soybean and palm oils resulted in higher LDL-cholesterol concentrations than did soybean (12% and 14%, respectively; P < 0.05) and canola (16% and 18%; P < 0.05) oils. Apolipoprotein B (P < 0.05) and A-I (P < 0.05) concentrations mirrored the pattern of LDL- and HDL-cholesterol concentrations, respectively. No significant effect on the total-to-HDL cholesterol ratio was observed for palm oil compared with the other dietary fats. HDL3 cholesterol was higher after palm oil than after partially hydrogenated and soybean oils (P < 0.05). Differences in measures of glucose and HDL intravascular processing attributable to dietary fat were small. CONCLUSION: Palm and partially hydrogenated soybean oils, compared with soybean and canola oils, adversely altered the lipoprotein profile in moderately hyperlipidemic subjects without significantly affecting HDL intravascular processing markers.

Intake of a single morning dose of standard and novel plant sterol preparations for 4 weeks does not dramatically affect plasma lipid concentrations in humans.

Recommendations for decreasing the risk of developing cardiovascular disease include increasing the intake of plant sterols and fish oil. The cholesterol-lowering action of plant sterols, when provided in a fish-oil fatty acids vehicle, remains to be investigated in humans. A randomized, crossover-feeding, single-blind trial was conducted in 30 subjects with mild-to-moderate hypercholesterolemia to study the effects on plasma lipids of 2 novel forms of plant sterols: those combined with, or esterified to, fish-oil fatty acids. The treatments were margarine (control), free plant sterols, plant sterols esterified to fatty acids from sunflower oil, plant sterols esterified to very long-chained fatty acids from fish oil, and plant sterols combined with the same amount of very long-chained fatty acids from fish oil. Each sterol-containing food (1.0-1.8 g plant sterols/d) was consumed for 29 d as a single dose with breakfast under staff supervision. Compared with the control treatment, none of the plant sterol preparations reduced plasma total cholesterol or LDL cholesterol, triacylglycerol, apolipoprotein A-I, apolipoprotein B, lipoprotein (a), or C-reactive protein concentration. Relative to the control phase, all plant sterols treatment increased the plasma HDL cholesterol concentration (P < 0.05) by approximately 8%. In conclusion, because standard forms of plant sterols did not reduce plasma cholesterol concentrations, the efficacy of the new formulation of plant sterols cannot be confirmed from the present study design, where plant sterols were given as a single morning dose.

Hypocholesterolemic effect of physically refined rice bran oil: studies of cholesterol metabolism and early atherosclerosis in hypercholesterolemic hamsters.

Physically refined rice bran oil containing 2-4% nontriglyceride components as compared to other vegetable oils appears to be associated with lipid lowering and antiinflammatory properties in several rodent, primate and human models. These experiments were designed to investigate possible mechanisms for the hypocholesterolemic effect of the physically refined rice bran oil and to examine its effect on aortic fatty streak formation. In the first experiment, 30 hamsters were fed, for 8 weeks, chow-based diets plus 0.03% added cholesterol and 5% (wt/wt) coconut, canola, or physically refined rice bran oil (COCO, CANOLA or PRBO animal groups, respectively). Both plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were significantly reduced in PRBO but not in CANOLA relative to COCO. PRBO also showed a significant 15-17% reduction in cholesterol absorption and significant 30% increase in neutral sterol (NS) excretion with no effect on bile acid (BA) excretion. Both CANOLA and PRBO showed a significant 300-500% increase in intestinal 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and significant (>25%) decrease in hepatic HMG-CoA reductase activities with respect to COCO. In a second experiment, 36 hamsters were fed chow-based diets with 0.05% added cholesterol, 10% coconut oil and 4% additional COCO, CANOLA or PRBO. Relative to COCO and CANOLA, plasma TC and LDL-C were significantly reduced in PRBO. Early atherosclerosis (fatty streak formation) was significantly reduced (48%) only in PRBO, relative to the other two. These results suggest that the lipid lowering found in PRBO is associated with decreased cholesterol absorption, but not hepatic cholesterol synthesis, and that the decrease in fatty streak formation with this oil may be associated with its nontriglyceride components not present in the other two diets.

Soy protein favorably affects LDL size independently of isoflavones in hypercholesterolemic men and women.

We assessed the independent effect of soy protein relative to animal protein and of isoflavones on various electrophoretic characteristics of LDL particles. LDL particles were characterized by polyacrylamide gradient gel electrophoresis in 36 moderately hypercholesterolemic men and women (LDL cholesterol > 3.36 mmol/L). All subjects consumed in random order each of the four diets (soy protein depleted of isoflavones, soy protein enriched in isoflavones, animal protein with no added isoflavones, and animal protein with added isoflavones) for 6 wk. Consumption of soy protein was associated with a larger LDL peak particle size relative to animal protein (P < 0.01). Soy protein also decreased the cholesterol levels in LDL < 25.5 nm by 12.3% (P < 0.001) and increased cholesterol levels in LDL > 26.0 nm by 14.3% (P < 0.05) relative to animal protein. Isoflavones did not affect these LDL particle characteristics. Soy protein shifted LDL particle distribution to a less atherogenic pattern and this effect is independent of soy's isoflavone component.

Influence of hydrogenated fat and butter on CVD risk factors: remnant-like particles, glucose and insulin, blood pressure and C-reactive protein.

Dietary trans fatty acids/partially-hydrogenated fat has been associated with increased risk of developing cardiovascular disease (CVD), possibly greater than predicted from changes in lipoprotein levels. To explore this issue further potential risk factors were assessed in subjects provided with each of six diets in randomized order containing as the major source of fat: soybean oil, semi-liquid margarine, soft margarine, shortening, traditional stick margarine or butter. Plasma fatty acid profiles reflected diet, with triglyceride and phospholipid subfractions affected to a greater extent than cholesteryl ester. Non-fasting LDL-cholesterol levels were 144+/-27, 141+/-27, 146+/-26, 148+/-30, 151+/-29 and 165+/-31 mg/dl (P<0.001) and total cholesterol/HDL-cholesterol ratios were 5.50+/-1.25, 5.54+/-1.50, 5.69+/-1.29, 5.82+/-1.40, 6.11+/-1.30 and 5.94+/-1.43 (P=0.011), respectively, whereas other lipoprotein levels were not significantly different. Remnant-like particles levels were unaffected by dietary fat, either in the fasting or non-fasting state. Differences in fasting insulin and glucose levels were small and would not be predicted to have a large impact on glucose homeostasis. There was no significant effect of dietary fat type on C-reactive protein levels or blood pressure. These data suggest that, as previously demonstrated, the major CVD risk factor adversely affected by dietary trans fatty acids/partially-hydrogenated fat is LDL-cholesterol levels and total cholesterol/HDL-cholesterol ratios.