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Naringenin (NGEN) is a natural flavonoid aglycone of naringin that has been reported to have a wide range of pharmacological properties, such as antioxidant activity and free radical scavenging capacity. The aim of this study was to investigate the protective effect of NGEN on oxidative and inflammatory parameters, as well as to evaluate the hydrolysis of adenine nucleotides in kidney and platelet membranes of rats exposed to a hypercholesterolemic diet (HCD) for 90 days. Kidney oxidative stress and mRNA expression of the ectonucleoside triphosphate diphosphohydrolases (NTPDases), ecto-5'-nucleotidase (CD73), inducible NO synthase (iNOS), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6) and the nuclear factor kappa B (NF-κB) genes were evaluated by real time RT-PCR. The co-administration of NGEN (50 mg kg(-1)) for 90 days significantly prevented renal failure in HCD rats as indicated by an improvement of renal markers. Histopathological observation findings are also consistent with these effects. Moreover, NGEN (50 mg kg(-1)) significantly decreased the lipid profile and inhibited pro-oxidant and inflammation marker levels in the kidney of HCD rats. Furthermore, the NTPDase activities were significantly decreased in platelets and kidney membranes of HCD-treated rats and these alterations were improved by NGEN. In conclusion, this study suggests that naringenin can potentially improve the renal failure and platelet alterations observed in rats fed a hypercholesterolemic diet probably through its antioxidant effects.

OBJECTIVE Diet may influence the risk of gestational diabetes mellitus (GDM), but inconsistent findings have been reported. The purpose of this study was to synthesize evidence from observational studies on the associations between dietary factors and GDM. RESEARCH DESIGN AND METHODS Medline and Embase were searched for articles published until January 2015. We included observational studies of reproductive-aged women that reported on associations of maternal dietary intake before or during pregnancy, including energy, nutrients, foods, and dietary patterns, with GDM. All relevant results were extracted from each article. The number of comparable studies that adjusted for confounders was insufficient to perform a meta-analysis. RESULTS The systematic review included 34 articles comprising 21 individual studies (10 prospective cohort, 6 cross-sectional, and 5 case-control). A limited number of prospective cohort studies adjusting for confounders indicated associations with a higher risk of GDM for replacing 1–5% of energy from carbohydrates with fat and for high consumption of cholesterol (≥300 mg/day), heme iron (≥1.1 mg/day), red and processed meat (increment of 1 serving/day), and eggs (≥7 per week). A dietary pattern rich in fruit, vegetables, whole grains, and fish and low in red and processed meat, refined grains, and high-fat dairy was found to be beneficial. The current evidence is based on a limited number of studies that are heterogeneous in design, exposure, and outcome measures. CONCLUSIONS The findings support current dietary guidelines to limit consumption of foods containing saturated fat and cholesterol, such as processed meat and eggs, as part of an overall balanced diet. Further large prospective studies are warranted.

Background The goal of this study was to establish an apolipoprotein E-deficient (ApoE -/- ) rat model. Methods The ApoE -/- rat was created by TALEN-mediated gene targeting in the genetic background of Sprague Dawley rat. Six-to eight-week-old male rats were used in the experiments (n = 10 in each group). Results After fed with high-cholesterol diet (HCD) for 12 weeks, the ApoE -/- rats displayed typical dyslipidemia. In contrast, HCD failed to induce hypercholesterolemia in wild-type rats. However, there was no obvious atherosclerotic lesion in oil red O-stained en face aortas and the aortic root sections in both genetic types of rats. Interestingly, partial ligation caused the formation of plaques consist of lipid and macrophages in carotid arteries from ApoE -/- rats, but induced the neointimal hyperplasia in wild-type rats. Additionally, we found that HCD slightly increased the expression of adhesion molecules, while partial ligation dramatically upregulated these molecules. Conclusions The ApoE -/- rat is a novel model for dyslipidemia and could also be used in the research of atherosclerosis.

Lorcaserin (LORCA) and liraglutide (LIRA) were evaluated in a novel diet-induced obese (DIO) rat model fed a free choice (FC) diet, that presents rats with the options between control chow (CC) or high fat/cholesterol (HFC) diet, and normal water (NW) or 10% fructose water (FW). After 8 weeks of FC diet-induced obesity/insulin resistance, rats were maintained on FC diet and treated daily for 5 weeks with vehicle, LORCA 18 mg/kg orally or LIRA 0.4 mg/kg subcutaneously. Compared to CC diet, FC diet resulted in higher intake of HFC and FW, and significantly higher caloric intake and overweight. LIRA induced a lower HFC/FW and higher CC/NW intake, a 12% body weight loss (P 0.01 vs. FC) and 40% lower visceral fat mass (P 0.001). LORCA only reduced HFC intake and body weight gain (P 0.001 vs. FC). FC diet raised HOMA-IR index and plasma leptinemia by 66% and 165% (both P 0.05 vs. CC), which were 50% and 70% lower with LIRA (both P 0.05 vs. FC), but unchanged by LORCA. LIRA and LORCA significantly improved FC diet-induced glucose intolerance. Only LIRA reduced liver fatty acids, triglycerides, and cholesterol by 68, 71 and 51% (all P 0.001). FC diet also induced a diastolic dysfunction with reduced E/A ratio (P 0.01 vs. CC), which was improved by LIRA and LORCA (both P 0.01 vs. FC). LIRA also raised fractional shortening (P 0.01 vs. FC). Overall, LIRA showed superior cardiometabolic benefits than LORCA in DIO rats under the FC diet, a model that will be useful to evaluate novel drugs targeting obesity and co-morbidities.

With the improvement of people's living standards and the change of dietary habits, Non-alcoholic fatty liver disease (NAFLD) has gradually become one of the liver diseases that endanger human health around the world. However, there are no particularly effective drugs for NAFLD in the current market. Therefore, new drug candidates which could provide high efficacy and low toxicity are needed valuable for the prevention and treatment of NAFLD. 2,3,5,4'-tetrahydroxystilbence-2-O-β-D-glucoside (TSG) is extracted from Polygonum multiflorum Thunb., and has been widely used to treat a variety of chronic diseases in China. Recently, TSG has been reported to exert various biological activities in many studies, such as lipid-lowering, anti-inflammatory and anti-oxidant activities, which indicate that TSG may have the effect of improving NAFLD. After feeding 5% high cholesterol diet to 5 days post fertilization larval zebrafish for 10 days, hepatic steatosis larval zebrafish model was established successfully. Then the effect of TSG on the improvement of hepatic steatosis larval zebrafish was studied. Moreover, the potential mechanism of TSG on anti-NAFLD effect were studied using RT-qPCR methods from multiple pathogenesis aspects of lipogenesis, lipid-lowering, inflammation, and oxidant stress. To conclude, TSG attenuates hepatic steatosis via regulating lipid metabolism related pathway, IKKβ/NF-κB anti-inflammatory pathway and Keap1-Nrf2 anti-oxidant pathway.

Milk sphingomyelin (SM), a polar lipid (PL) component of milk fat globule membranes, is protective against dyslipidemia. However, it is unclear whether ingestion of milk PLs protect against atherosclerosis. To determine this, male LDLr-/- mice (age 6 weeks) were fed ad libitum either a high-fat, added-cholesterol diet (CTL; 45% kcal from fat, 0.2% cholesterol by weight; n=15) or the same diet supplemented with 1% milk PL (1% MPL; n=15) or 2% milk PL (2% MPL; n=15) added by weight from butter serum. After 14 weeks on diets, mice fed 2% MPL had significantly lower serum cholesterol (-51%) compared to CTL (P

The neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP) is vasoactive and cytoprotective and exerts immunoregulatory functions throughout the nervous, neuroendocrine cardiovascular and immune systems in health and disease. PACAP mainly acts through PAC1 receptor signaling in neuronal communication, but the role of PAC1 in immune regulation of atherosclerosis is not known. Here, we generated PAC1(−/−)/ApoE(−/−) mice to test, whether PAC1(−/−) influences plasma cholesterol-/triglyceride levels and/or atherogenesis in the brachiocephalic trunk (BT) seen in ApoE(−/−) mice, under standard chow (SC) or cholesterol-enriched diet (CED). Furthermore, the effect of PAC1(−/−), on inflammatory, autophagy-, apoptosis- and necroptosis-relevant proteins in atherosclerotic plaques was determined. In plaques of PAC1(−/−)/ApoE(−/−) mice fed a SC, the immunoreactivity for apoptotic, autophagic, necroptotic and proinflammatory proteins was increased, however, proliferation was unaffected. Interestingly, without affecting hyperlipidemia, PAC1(−/−) in ApoE(−/−) mice remarkably reduced CED-induced lumen stenosis seen in ApoE(−/−) mice. Thus, PAC1(−/−) allows unchecked inflammation, necroptosis and decreased proliferation during SC, apparently priming the BT to develop reduced atheroma under subsequent CED. Remarkably, no differences in inflammation/necroptosis signatures in the atheroma under CED between PAC1(−/−)/ApoE(−/−) and ApoE(−/−) mice were observed. These data indicate that selective PAC1 antagonists should offer potential as a novel class of atheroprotective therapeutics, especially during hypercholesterolemia.

Incidence of nonalcoholic fatty liver disease is increasing worldwide. Activation of the NLRP3 inflammasome is central to the development of diet-induced nonalcoholic steatohepatitis (NASH). We investigated whether benzyl isothiocyanate (BITC) ameliorates diet-induced NASH and the mechanisms involved. C57BL/6 J mice fed a high-fat diet containing cholesterol and cholic acid (HFCCD) and Kupffer cells stimulated with LPS and cholesterol crystals (CC) were studied. LPS/CC increased the expression of the active form of caspase 1 (p20) and the secretion of IL-1β by Kupffer cells, and these changes were reversed by MCC950, an NLRP3 inflammasome inhibitor. LPS/CC-induced NLRP3 inflammasome activation and IL-1β production were dose-dependently attenuated by BITC. BITC decreased cathepsin B release from lysosomes and binding to NLRP3 induced by LPS/CC. Compared with a normal diet, the HFCCD increased serum levels of ALT, AST, total cholesterol, and IL-1β and hepatic contents of triglycerides and total cholesterol. BITC administration (0.1% in diet) reversed the increase in AST and hepatic triglycerides in the HFCCD group. Moreover, BITC suppressed lipid accumulation, macrophage infiltration, fibrosis, crown-like structure formation, and p20 caspase 1 and p17 IL-1β expression in liver in the HFCCD group. These results suggest that BITC ameliorates HFCCD-induced steatohepatitis by inhibiting the activation of NLRP3 inflammasome in Kupffer cells and may protect against diet-induced NASH.

Silybin shows good effects against obesity and metabolic syndrome, but the systemic modulation effect of silybin has not been fully revealed. This study aims to investigate the metabolic regulation by silybin of nonalcoholic fatty liver disease (NAFLD). C57BL/6 J mice were fed a high-fat/high-cholesterol diet for 8 weeks and treated with silybin (50 or 100 mg/kg/day) and sodium tauroursodeoxycholate (TUDCA, 50 mg/kg/day) by gavage for the last 4 weeks. Blood biochemical indexes and hepatic lipid measurement as well as Oil red O staining of the liver were conducted to evaluate the model and the lipid-lowering effect of silybin and TUDCA. Furthermore, serum and liver samples were detected by a metabolomic platform based on gas chromatography-mass spectrometry (GC/MS). Multivariate/univariate data analysis and pathway analysis were used to investigate differential metabolites and metabolic pathways. The results showed that the mouse NAFLD model was established successfully and that silybin and TUDCA significantly lowered both serum and hepatic lipid accumulation. Metabolomic analysis of serum and liver showed that a high-fat/high-cholesterol diet caused abnormal metabolism of metabolites involved in lipid metabolism, polyol metabolism, amino acid metabolism, the urea cycle and the TCA cycle. Silybin and TUDCA treatment both reversed metabolic disorders caused by HFD feeding. In conclusion, a high-fat/high-cholesterol diet caused metabolic abnormalities in the serum and liver of mice, and silybin treatment improved hepatic lipid accumulation and modulated global metabolic pathways, which provided a possible explanation of its multiple target mechanism.

Background Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases that may progress to liver fibrosis or cancer. The present study aimed to investigate the role of microRNA-125b-5p (miR-125b-5p) in NAFLD and to further explore underlying molecular mechanisms. Methods A mouse model of NAFLD was constructed by high cholesterol diet feeding and a cell-model was developed by treating the mouse liver cell line NCTC1469 with palmitic acid. Gain- and loss-of-function experiments were performed to determine the effects of miR-125b-5p, integrin α8 (ITGA8), and the RhoA signaling pathway on liver fibrosis in NAFLD. After the expression levels of miR-125b-5p, ITGA8, and RhoA were determined, liver fibrosis was evaluated in vivo and in vitro. The binding relationship of miR-125b-5p and ITGA8 was then validated. Finally, miR-125b-5p promoter methylation in NAFLD liver tissues and cells was determined. Results In NAFLD clinical samples, mouse model, and cell-model, miR-125b-5p expression was reduced, while ITGA8 expression was increased. Moreover, miR-125b-5p targeted and downregulated ITGA8, leading to inhibition of the RhoA signaling pathway. In NAFLD liver tissues and cells, the CpG island in the miR-125b-5p promoter was methylated, causing epigenetic silencing of miR-125b-5p. Both miR-125b-5p silencing and ITGA8 overexpression promoted in vitro and in vivo liver fibrosis in NAFLD via activation of the RhoA signaling pathway. Conclusions Collectively, epigenetic silencing of miR-125b-5p upregulates ITGA8 expression to activate the RhoA signaling pathway, leading to liver fibrosis in NAFLD.

Aims Imatinib is an effective tyrosine kinase inhibitor which has different therapeutic actions. The recent work demonstrated the possible beneficial effects of imatinib on the progression of atherosclerosis, endothelial dysfunction, and hypercholesterolemia-associated liver damage in rabbits. Main methods Animals had been distributed in 4 groups: group 1 (non-treated): animals fed regular diet; group 2 high cholesterol [HC]: animals fed 1% cholesterol supplemented diet for 30 days; group 3 (HC-Imatinib): animals fed 1% cholesterol supplemented diet+imatinib (0.01 g/kg daily, p.o) for 30 days; group 4 (Imatinib): animals fed regular diet with imatinib (0.01 g/kg daily, p.o). After thirty days, tissue samples and blood were isolated to be detected biochemically, histologically, and for in vitro analysis. Key findings HC exhibited significant elevations in serum lipid parameters, CRP, ALT, AST and ALP. Additionally, HC induced significant increases for aortic and hepatic MDA, aortic NO and hepatic PDGFR-β, while significantly exhibited reductions in aortic and hepatic GSH, SOD and hepatic PPARγ1. Moreover, HC produced impairment in ACh-enhanced aortic relaxation and aortic pathological changes. Histopathological examination of HC-fed rabbits revealed hepatic steatosis compared with non-treated group. Imatinib administration exhibited significant decreases in serum lipid parameters, CRP, ALT, AST and ALP. Additionally, imatinib induced significant decreases for aortic and hepatic MDA, aortic NO and hepatic PDGFR-β, while significantly exhibited elevations in aortic and hepatic GSH, SOD and hepatic PPARγ1 compared with HC animals. Furthermore, imatinib significantly protected against HC produced attenuation in ACh-induced aortic relaxation and pathological changes in aortic and hepatic tissues. Interestingly, imatinib could return serum CRP, ALP, hepatic SOD and PDGFR-β to basal values. Significance The recent observation reports that imatinib could have beneficial effect against atherosclerosis progression, vascular malfunction, and liver damage in high cholesterol diet (HCD)-fed rabbits.

The programming of hepatic lipid dysfunction in response to early cholesterol exposure and the influencing effects of postnatal diet is evaluated in apoEIn two separate studies, female mice are assigned to a standard chow (S) or a cholesterol-enriched chow (C) diet during gestation and lactation. Male offspring from each dam are weaned on a postnatal S or a hypercaloric western (W) diet resulting in four experimental groups: S-S and C-S (Experiment 1) and S-W and C-W (Experiment 2). At weaning, litters from hypercholesterolemic mothers weighed less (p 0.05) and pups had higher blood lipids, glucose, and hepatic cholesterol compared with pups from S-fed mothers. Adult C-S offspring demonstrate an atherogenic lipid profile and increased (p 0.05) hepatic cholesterol and triglyceride content with altered lipid regulatory mRNA expression and protein content compared with S-S offspring. Alternatively, no difference (p 0.05) is observed between S-W and C-W in serum and hepatic lipid profiles; however, serum AST and ALT are higher (p 0.05) in C-W versus S-W offspring.The degree of hepatic lipid deposition observed in adult offspring exposed to excessive early cholesterol is influenced by the postnatal diet.

This study investigated the chemical composition, in vivo antioxidant, and antihyperlipidemic potential of Ajwa date polyphenol extract (DPE). Chemical analysis revealed that the Ajwa dates contain substantial amounts of carbohydrates, energy, potassium, iron, polyphenols, and flavonoids. In vivo studies showed that feeding rats with cholesterol-rich diets significantly (p ≤ 0.05) increased their body and liver weights, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), very-low-density lipoprotein cholesterol (VLDL-C), and triglycerides (TG) in plasma and liver, and reduced the high-density lipoprotein cholesterol (HDL-C) content and antioxidant enzyme activities. However, oral administration of 25, 50, and 100 mg DPE/kg body weight to hypercholestrolemic rats, significantly (p ≤ 0.05) reduced their body and liver weights, total hepatic cholesterol, LDL-C, VLDL-C, and triglycerides. Furthermore, treatment with DPE improved (p ≤ 0.05) the HDL-C concentration and antioxidant enzyme activity in a concentration-dependent fashion, thereby regulating lipid profiles, enhancing the antioxidant defense system. Overall, DPE showed significant (p ≤ 0.05) nutritional, antioxidants, and antihyperlipidemic benefits. PRACTICAL APPLICATIONS: Coronary heart disease is the leading cause of death in the world. Consumption of fruits and vegetables rich in polyphenol have shown to exert cardio-protective effect. This work revealed that phenolic extracts of Ajwa dates have positive impacts on the health as it reduced TC, LDL-C, and lipids VLDL-C and improved HDL-C and the antioxidant defense system in rats. The findings of this study could aid in the profound understanding of the nutritional and health potentials of Ajwa dates and thus could help in utilization of these valuable fruits for the prevention and curing of cardiovascular diseases.

Statins are a class of lipid-lowering drugs commonly used in the prevention of cardiovascular diseases. However, statin therapy presents many limitations, which have led to an increased interest in non-drug therapies, such as probiotics, to improve blood cholesterol levels. Indeed, probiotic strains such as

The aim of the present work was to assess consumers' willingness to pay for reformulated frankfurters in the context of the implementation of nutritional warnings. Images of frankfurter packages were designed using a fractional factorial design with 5 2-level variables: brand type, sodium reduction, saturated fat reduction, fibre claim and cholesterol claim. An online study with 548 consumers was implemented with Chilean participants, who were asked to indicate how much they would be willing to pay for each of the packages. Data were analysed using analysis of variance and hierarchical cluster analysis. Willingness to pay was significantly affected by brand type and sodium and fat reduction, whereas fibre and cholesterol claim did not have a significant effect. These results suggest that in the context of the implementation of nutritional warnings reformulation of processed meat products should focus on the reduction of key nutrients, although consumers may not be willing to pay a higher price for reformulated products.

Heating oils and fats for a considerable length of time results in chemical reactions, leading to the aggravation of a free radical processes, which ultimately contributes to atherosclerosis. Our study focused on elucidating the effect of feeding heated oils with or without dietary cholesterol on the development of atherosclerosis in rabbits. We heated palm olein and corn oil at 180 °C for 18 h and 9 h per day, respectively, for two consecutive days. Next, 20 male rabbits were divided into four groups and fed the following diet for 12 weeks: (i) heated palm olein (HPO); (ii) HPO with cholesterol (HPOC); (iii) heated corn oil (HCO); and (iv) HCO with cholesterol (HCOC). Plasma total cholesterol (TC) was significantly lower in the HCO group compared to the HCOC group. Atherosclerotic lesion scores for both fatty plaques and fatty streaks were significantly higher in the HCO and HCOC groups as compared to the HPO and HPOC groups. Additionally, fibrous plaque scores were also higher in the HCO and HCOC groups as compared to the HPO and HPOC groups. These results suggest that heated palm oil confers protection against the onset of atherosclerosis compared to heated polyunsaturated oils in a rabbit model.

The aim of this study was to investigate the effect of Lactobacillus plantarum and Bacillus coagulans on serum lipid profile and lowering potential of probiotic in hypercholesterolemic rats. Twenty-eight male Wistar rats were divided into four groups as follows: (1) control group, fed standard commercial diet; (2) HC group, fed high-cholesterol diet; (3) HC + LP group, fed high-cholesterol diet and gavaging of L. plantarum; and (4) HC + BC group fed high-cholesterol diet and gavaging of B. coagulans. After 28 and 50 days, serum lipid profile; serum ALT and AST; the body and organ weights; fecal total count; Enterobacteriaceae, L. plantarum, and B. coagulans counts; and blood glucose tolerance were measured. We observed that levels of triglyceride, cholesterol, LDL, VLDL, and atherogenic index in serum were significantly lower in the HC + probiotic groups. Also, serum ALT and AST were significantly decreased in probiotic-treated groups. In addition, we found that feeding of a high-cholesterol diet for 50 days produced significant increases in the body weight, in addition to the fact that the administration of L. plantarum and B. coagulans has considerably reduced the body weight gain. B. coagulans and L. plantarum can survive passing through the upper-gastrointestinal tract after oral feeding to the rats and colonized in their colon. These bacteria could be exploited as a potential biotherapeutic remedy to reduce TC, TG, LDL, VLDL, and atherogenic index in hypercholesterolemic condition.

Peroxisome proliferator-activated receptor α (PPARα) is involved in the regulation of fatty acid and cholesterol metabolism. A high-cholesterol (HC) diet increases the risk of developing cardiovascular diseases (CVD); however, it is unclear whether the toxic effects of cholesterol involve changes in thrombotic factor expression, and whether PPARα is necessary for such effects. To investigate this possibility, we fed a HC diet to wild-type (WT) and Ppara-null mice and measured cholesterol and triglyceride contents, liver histology, serum/plasma levels of coagulation factors, hepatic expression of the coagulation factors, liver/serum sulfatide levels, hepatic sulfatide metabolism, hepatic expression of lipid transporters, and hepatic oxidative stress and its relating enzymes. In Ppara-null mice, the HC diet caused triglyceride accumulation and exacerbated inflammation and oxidative stress in liver, increased levels of coagulation factors, including tissue factor, plasminogen activator inhibitor-1 and carboxypeptidase B2 in blood and liver, and decreased levels of anti-thrombotic sulfatides in serum and liver. These changes were much less marked in WT mice. These findings imply that cholesterol overload exerts its toxic effects at least in part by enhancing thrombosis, secondary to abnormal hepatic lipid metabolism, inflammation, and oxidative stress. Moreover, we reveal for the first time that PPARα can attenuate these toxic effects by transcriptional regulation of coagulation factors and sulfatides, in addition to its known effects of controlling lipid homeostasis and suppressing inflammation and oxidative stress. Therapies aimed at activating PPARα might prevent HC diet-induced CVD through modulating various pro- and anti-thrombotic factors.

We hypothesized that schizandrin (SCH) A, a lignan found in the fruits of the Schisandra genus, would exert protective effects against high-fat and high-cholesterol (HFHC) diet–induced nonalcoholic fatty liver disease (NAFLD) via regulation of lipid metabolism and oxidative stress. To test our hypothesis, male C57BL/6J mice were fed an HFHC diet with or without SCH A for 15 weeks. There were no significant differences in food intake, body weight, fat mass, and plasma total cholesterol level between the 2 groups. However, supplementation of SCH A significantly decreased levels of plasma free fatty acid and triglyceride, whereas plasma high-density lipoprotein cholesterol level was increased in the SCH A-supplemented mice. Moreover, hepatic free fatty acid, triglyceride, and cholesterol content, as well as hepatic lipid droplet accumulation, were markedly lower in the SCH A group in contrast to the control group. Activity of hepatic enzymes involved in fatty acid and triglyceride synthesis was significantly decreased by SCH A supplementation, whereas SCH A markedly increased hepatic β-oxidation and fatty acid oxidation-related gene expression as well as fecal excretion of free fatty acid and triglyceride. SCH A also significantly increased expression of genes involved in cholesterol homeostasis (biliary cholesterol excretion and cholesterol efflux to high-density lipoprotein) in the liver. Moreover, SCH A significantly decreased hepatic lipid peroxidation, which was accompanied by increased hepatic antioxidant enzymes activity. These results suggest that SCH A could alleviate HFHC diet–induced NAFLD by regulating hepatic lipid metabolism and oxidative stress as well as fecal lipid excretion.

Aims A long-term high-fat/cholesterol (HFC) diet leads to hepatic insulin resistance (IR), which is associated with autonomic dysfunction and cardiovascular diseases risk increasing. However, whether this occurs in Tibetan minipigs remains unknown. We tested that a long-term HFC diet caused hepatic IR and promote cardiovascular disorders in Tibetan minipigs, and are associated with the reduction of cardiovagal tone and baroreflex sensitivity (BRS). Methods Male Tibetan minipigs were fed either a standard diet or a HFC diet, and were euthanized at 12 weeks. Thereafter, the minipigs were tested for biochemical blood indices, glucose tolerance, blood pressure, heart rate variability (HRV), BRS, and insulin receptor substrate (IRS)-associated gene and protein expression levels, as well as cardiac function. Results HFC-fed minipigs developed IR by increasing body weight, total cholesterol, fasting blood glucose and insulin levels, and nonesterified fatty acid (NEFA) and high sensitive C-reactive protein (hs-CRP) levels, glucose intolerance. Increased adipose cell size, hepatic fat deposition, malondialdehyde (MDA) content and NEFA level, down-regulation of IRS1, IRS2, PI3K, Akt, p-Akt, Glut2 and PGC1ɑ expression concomitant with up-regulation of mTOR, GSK3β, TNF-ɑ, FOXO1, p-mTOR and p-p70S6K expression in the liver tissue, as well as hypertension and left ventricular diastolic dysfunction were observed in HFC-fed minipigs. HRV parameters and BRS values were further significantly reduced. Furthermore, multiple linear regression analysis showed that the development of hepatic IR toward cardiovascular disease was associated with low HFnu, RMSSD, BRS and LV −dp/dtmax, high NEFA, high hepatic TG content. Conclusion These data suggest that HFC-fed Tibetan minipigs develop hepatic IR and promote cardiovascular disorders, and are associated with lower cardiovagal tone and BRS.

While the impact of dietary cholesterol on the progression of atherosclerosis has probably been overestimated, increasing evidence suggests that dietary cholesterol might favor the transition from blunt steatosis to non-alcoholic steatohepatitis (NASH), especially in combination with high fat diets. It is poorly understood how cholesterol alone or in combination with other dietary lipid components contributes to the development of lipotoxicity. The current study demonstrated that liver damage caused by dietary cholesterol in mice was strongly enhanced by a high fat diet containing soybean oil-derived ω6-poly-unsaturated fatty acids (ω6-PUFA), but not by a lard-based high fat diet containing mainly saturated fatty acids. In contrast to the lard-based diet the soybean oil-based diet augmented cholesterol accumulation in hepatocytes, presumably by impairing cholesterol-eliminating pathways. The soybean oil-based diet enhanced cholesterol-induced mitochondrial damage and amplified the ensuing oxidative stress, probably by peroxidation of poly-unsaturated fatty acids. This resulted in hepatocyte death, recruitment of inflammatory cells, and fibrosis, and caused a transition from steatosis to NASH, doubling the NASH activity score. Thus, the recommendation to reduce cholesterol intake, in particular in diets rich in ω6-PUFA, although not necessary to reduce the risk of atherosclerosis, might be sensible for patients suffering from non-alcoholic fatty liver disease.

Intrinsic cardioprotective mechanisms become activated in the early diabetes mellitus (DM) and this may protect the heart from ischemia/reperfusion (I/R) similarly as in case of ischemic preconditioning. However, this protection may by blunted in the presence of cardiovascular risk factors. Assuming that hypercholesterolemia (HCH) frequently accompanies DM, this study extends findings from separate models of DM and HCH by investigation the impact of HCH on DM-induced changes, including those of compensatory nature, in rat heart and its mitochondria. We used a factorial design with all combinations of treatment factors DM and HCH: control rats (C) and streptozotocin-treated rats (DM), both on standard chow (C and DM) and fed fat-cholesterol diet (HCH and DM-HCH). Isolated, Langendorff perfused hearts were subjected to 30 min global ischemia followed by reperfusion. Significantly increased levels of cholesterol in DM-HCH after I/R injury abrogated compensatory fluidization characteristic of DM mitochondria membranes. Concomitantly, the mitochondrial Mg

Whole egg is a food source of dietary cholesterol and inconsistent research findings exist about the effect of dietary cholesterol from whole egg on blood cholesterol concentration. We assessed the effect of co-consuming cooked whole egg (CWE) on dietary cholesterol absorption from two randomized-crossover studies. For study 1, 16 men consumed raw vegetables with no egg, 75 g CWE, or 150 g CWE. For study 2, 17 women consumed cooked vegetables with no egg or 100 g CWE. Triacylglycerol-rich lipoprotein fractions (TRL) were isolated from collected blood. In study 1, total-cholesterol areas under the curve (AUC)0&ndash, 10h in TRL were not different but triacylglycerol AUC0&ndash, 10h in TRL was greater for 150 g CWE vs. 75 g CWE and no egg. Similarly, in study 2, total-cholesterol AUC0&ndash, 10h in TRL was not different but triacylglycerol AUC0&ndash, 10h in TRL was greater for 100 g CWE vs. no egg. In both studies, whole egg consumption did not affect plasma total-cholesterol AUC0&ndash, 10h, while triacylglycerol AUC0&ndash, 10h was increased. These results suggest that the dietary cholesterol in whole egg was not well absorbed, which may provide mechanistic insight for why it does not acutely influence plasma total-cholesterol concentration and is not associated with longer-term plasma cholesterol control.

Freshwater clam (Corbicula fluminea) is a traditional liver-protective food in Asia. Recent studies have renewed attention on high cholesterol accumulation and dysregulated cholesterol synthesis in the liver as a critical factor in the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH). In this study, we investigated the protective effects of freshwater clam extract (FCE) and its fat fraction (FCE oil) on high-fat, high-cholesterol and cholic acid (HFHC) diet-induced lean steatohepatitis in mice. Mice were fed a HFHC diet containing FCE or FCE oil for 6 weeks. FCE, but not FCE oil, feeding reduced liver injury as indicated by decreased plasma alanine aminotransferase activity. Liver total cholesterol accumulation was reduced after FCE and FCE oil treatment. Accumulation of squalene and desmosterol, the precursors of cholesterol, in the liver was reduced by FCE but not by FCE oil. The caspase-1 (p10) and interleukin (IL)-1β (p17) protein expressions in the liver were suppressed by both FCE and FCE oil. Therefore, FCE may act as functional food that can reduce steatohepatitis and liver injury by reducing cholesterol accumulation, improving dysregulated cholesterol synthesis and attenuating inflammation.

BACKGROUND Individual variations of obesity-related traits can be a consequence of dietary influence on gene variants. METHODS This cross-sectional study aimed to evaluate (i) the effect of FTO rs9930506 on obesity and related parameters and (ii) the influence of diet on the above association in Malaysian adults. In total, 79 obese and 99 nonobese Malaysian adults were recruited. RESULTS In comparison with Chinese and Malays, Indians had significantly higher waist circumference (P ≤ 0.001 and P = 0.016), waist-hip ratio (P = 0.001 and P < 0.001), body fat percentage (P = 0.001 and P = 0.042), fasting insulin (P = 0.001 and P = 0.001), homeostatic model assessment-insulin resistance (P = 0.001 and P = 0.001) and lower high-density lipoprotein-cholesterol levels (P < 0.001 and P < 0.001), respectively. Indians consumed significantly lower dietary cholesterol (P = 0.002), percentage energy from protein (P < 0.001) and higher fibre (P = 0.006) compared to the other two groups. Malaysian Indians expressed the highest risk allele frequency (G) of FTO rs9930506 compared to the Malays and the Chinese (P < 0.001). No significant association was found between FTO rs9930506 and obesity (dominant model). Risk allele carriers (G) consumed significantly lower vitamin E (P = 0.020) and had a higher fibre intake (P = 0.034) compared to the noncarriers (A). Gene-diet interaction analysis revealed that risk allele carriers (G) had lower high sensitivity C-reactive protein (hsCRP) levels with higher energy from protein (≥14% day-1 ; P = 0.049) and higher vitamin E (≥5.4 mg day-1 ; P = 0.038). CONCLUSIONS The presence of the risk allele (G) of FTO rs9930506 was not associated with an increased risk of obesity. Malaysian Indians had a significantly higher frequency of the risk allele (G). Indian participants expressed higher atherogenic phenotypes compared to Chinese and Malays. FTO rs9930506 may interact with dietary protein and vitamin E and modulate hsCRP levels.

Background The globally rising obesity epidemic is associated with a broad spectrum of diseases including atherosclerosis and non-alcoholic fatty liver (NAFL) disease. In the past, research focused on the vasculature or liver, but chronic systemic effects and inter-organ communication may promote the development of NAFL. Here, we investigated the impact of confined vascular endothelial injury, which produces highly inflamed aortic plaques that are susceptible to rupture, on the progression of NAFL in cholesterol fed rabbits. Methods Aortic atherosclerotic inflammation (plaque Gd-enhancement), plaque size (vessel wall area), and composition, were measured with in vivo magnetic resonance imaging (MRI) in rabbits fed normal chow or a 1% cholesterol-enriched atherogenic diet. Liver fat was quantified with magnetic resonance spectroscopy (MRS) over 3 months. Blood biomarkers were monitored in the animals, with follow-up by histology. Results Cholesterol-fed rabbits with and without injury developed hypercholesterolemia, NAFL, and atherosclerotic plaques in the aorta. Compared with rabbits fed cholesterol diet alone, rabbits with injury and cholesterol diets exhibited larger, and more highly inflamed plaques by MRI (P

Summary Background & aims The Scientific Report of 2015 Dietary Guidelines Advisory Committee recommended the elimination of dietary cholesterol limits. However, cholesterol intake increases during pregnancy and studies regarding the association between dietary cholesterol and gestational diabetes mellitus (GDM) are limited. We evaluate the association of total dietary cholesterol and different sources of cholesterol intake during pregnancy, with GDM risk and blood glucose levels in a Chinese prospective cohort study. Methods A total of 2124 pregnant women from the Tongji Maternal and Child Health Cohort was included. A validated semi-quantitative food frequency questionnaire was used to assess dietary cholesterol intake prior to GDM diagnosis. GDM was diagnosed by the 75-g 2-h oral glucose tolerance test. Cubic-restricted spline function and logistic regression analyses were used to evaluate the association between dietary cholesterol intake during pregnancy and GDM. Generalized linear models were conducted to examine the associations of cholesterol intake with fasting blood glucose (FBG), 1-h post-load blood glucose (PBG) and 2-h PBG. Results The average dietary cholesterol intake was 379.1 mg/d, and cholesterol from eggs explained 64.2% of the variability. Total dietary cholesterol intake and cholesterol from eggs rather than other foods, were linearly associated with GDM risk, with adjusted OR for GDM of 2.10 (95%CI: 1.24, 3.58) for total cholesterol intake and 1.83 (95%CI: 1.08, 3.07) for cholesterol from eggs comparing the highest versus lowest quintile. A 100-mg/d increase in total cholesterol and cholesterol from eggs intake were associated with an increased GDM risk by 18% and 16%, respectively. Moreover, higher maternal dietary total cholesterol could increase FBG and 1-h PBG, while cholesterol from eggs increased FBG only. Conclusion Higher dietary cholesterol from eggs intake during pregnancy was associated with greater risk of GDM.

Introduction: The aim of study was to evaluate impact of long-term dietary cholesterol overload on the cholesterol homeostasis and liver regeneration. Material and Methods: Serum lipid parameters,14C-cholesterol incorporation, liver DNA synthesis and protein expression was determined in partially hepatectomized (PH) rats fed with a standard (SLD) or hypercholesterolemic (CHOL) diet. Results: 29-day intake of CHOL diet before PH produced increase in serum total cholesterol, LDL lipoprotein, and triglyceride concentration. PH provoked decrease in serum total cholesterol and triglyceride concentration in both groups. PH was associated with increase in serum ALT activity more pronounced in CHOL animals. Hepatic DNA synthesis was increased after PH in both groups, but lower in CHOL. Hypercholesterolemic diet reduced the absorption of radiolabelled cholesterol in intestine and then activity in blood and liver. The14C-cholesterol hepatic activities tend to increase after PH in both groups. CHOL diet produced up-regulation of Acyl-CoA:cholesterol acyltransferase-2 protein expression. PH was associated with increase of LDL receptor and Acyl-CoA:cholesterol acyltransferase-2 protein expression in both dietary groups. Discussion: Liver regeneration after PH is negatively influenced by CHOL diet. The increased uptake of cholesterol in the liver after PH associated with up-regulation of LDL receptor protein expression suggests preferential use of extrahepatic cholesterol by the liver.

The development of certain chronic metabolic diseases has been attributed to elevated levels of dietary cholesterol. However, decades of research in animal models and humans have demonstrated a high complexity with respect to the impact of dietary cholesterol on the progression of these diseases. Thus, recent investigations in non-alcoholic fatty liver disease (NAFLD) point to dietary cholesterol as a key factor for the activation of inflammatory pathways underlying the transition from NAFLD to non-alcoholic steatohepatitis (NASH) and to hepatic carcinoma. Dietary cholesterol was initially thought to be the key factor for cardiovascular disease development, but its impact on the disease depends partly on the capacity to modulate plasmatic circulating low-density lipoprotein (LDL) cholesterol levels. These studies evidence a complex relationship between these chronic metabolic diseases and dietary cholesterol, which, in certain conditions, might promote metabolic complications. In this review, we summarize rodent studies that evaluate the impact of dietary cholesterol on these two prevalent chronic diseases and their relevance to human pathology.

To investigate a high cholesterol diet in Alzheimer&rsquo, s disease (AD) mice, they were fed with (2% cholesterol) in five groups with a control group, AD mice group, AD mice plus Meretrix lusoria group, AD mice plus Geloina eros group, and, AD mice plus Corbicula fluminea group for three months, and treated with the fatty acid profiles of clams by gas chromatography (GC). The results showed that treatment with clams for three months reduced Fas/L and Caspase-3 in the Meretrix lusoria and Geloina eros groups, but Fas-associated death domain (FADD) and Caspase-8 were strongly reduced in the Geloina eros group. For the mitochondria-dependent apoptotic pathway, the reduction of apoptosis proteins were observed in the hearts of clams-treated AD mice. BAK and Caspase-9 was reduced in the Meretrix lusoria group, but Caspase-3 and Cytochrome-c were reduced in Geloina eros group. Enhancement of survival proteins p-AKT, p-IGF1R, p-PI3K, Bcl-XL, Bcl2, and the longevity SIRT1 signaling proteins, p-AMPK-&alpha, SIRT1, PGC1-&alpha, p-FOXO3 were observed in clams-treated mice and even more strongly enhanced in the Meretrix lusoria, Geloina eros and Corbicula fluminea groups. This study observed that the ingestion of clams caused a reduction of apoptosis proteins and enhancement of survival and SIRT1 signaling proteins in the hearts.

Alzheimer’s disease (AD) is one of the severe chronic diseases characterized with amyloid beta (Aβ) aggregation and formation of senile-plaque (SP) like structures. Numerous risk factors including trace metals and cholesterol in diet have been identified as potential players for the onset of Aβ aggregation. To further illustrate the effects of copper and cholesterol in AD pathology, we employed an AD model mouse strain (Tg2567) and examined the histological and biochemical changes in the mouse brains and blood. When supplied with 0.1 mg/L copper in drinking water and 2% cholesterol in the food, the mice showed significant deposit of amyloid beta (Aβ) and SP plaque formation in hippocampus and temporal cortex regions in their brains. These mice also showed elevated superoxide dismutase (SOD) activity and increased ceruloplasmin (CP) concentration, and reduced glutathione peroxidase (Gpx) activity in the blood. The physiological function tests indicated these mice were significantly impeded on learning and memory. We further examined the counteracting effects of 0.1 mg/L zinc and 1.0 mg/L fluvastatin (Cholesterol-lowering drug). The combination of zinc and fluvastatin effectively reversed the copper/cholesterol caused memory loss, anatomic amyloid deposits and the biochemical changes in the blood. This work provides more evidence of high-level cholesterol and copper as risk factors to trigger amyloid aggregation and mental dementia; zinc and reduction of food cholesterol levels can protect the animals from amyloid accumulation and learning impairment. The beneficial outcomes of zinc and fluvastatin could hint some potential usages in preventive measures for high-risk AD individuals, but further rigorous test are needed.

Rabbits are widely used for the study of atherosclerosis; however, the lack of a unified and quantitative analysis of atheroma limits data interpretation and comparisons between laboratories. In this study, we applied a simple quantitative method, referred to as the oil red O (ORO) dye-eluting method, for analysis of atherosclerotic plaques in freshly isolated aortas. It employs ORO staining of the plaques followed by elution of the dye that is subjected to quantitative measurement. Atherosclerosis was induced in rabbits by feeding a 1% (w/w) high cholesterol diet for 4 or 12 weeks. Thoracic aortas were isolated and sufficiently stained by ORO. These dyes were easily and completely extracted by 100% ethanol and quantified by spectrophotometric measurement at 510 nm. A series of cross-sectional slices at 100-µm intervals were counterstained by elastic van Gieson. It was found that there was a highly positive correlation between the dye concentration and the amount of plaque tissue, determined as volume of plaques (regression coefficient r2: 0.8792, p

We investigated the hypocholesterolemic and liver-protective effects of cooked and germinated whole mung beans. Hamsters were fed for 28 days on diets rich in saturated fatty acids and cholesterol, differing only in protein source (20%): casein, cooked whole mung bean, and germinated mung bean. After 28 days, we found reduced plasma concentrations of total cholesterol and non-HDL cholesterol, increased faecal cholesterol excretion, and reduced levels of asparagine aminotransferase and alanine aminotransferase enzymes in the liver. Reduction in hepatic lipid deposition was observed between each of the mung bean groups relative to the casein group. In addition, the animals of the geminated mung bean group showed a lack of inflammatory infiltrate and better vascularisation of the hepatic tissue. Results from this study show significant hypocholesterolemic and liver-protective properties of the mung bean, which are further enhanced after germination.

Cellular cholesterol metabolism, lipid raft formation, and lipoprotein interactions contribute to the regulation of immune-mediated inflammation and response to pathogens. Lipid pathways have been implicated in the pathogenesis of bacterial and viral infections, whereas altered lipid metabolism may contribute to immune dysfunction in autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis. Interestingly, dietary cholesterol may exert protective or detrimental effects on risk, progression, and treatment of different infectious and autoimmune diseases, although current findings suggest that these effects are variable across populations and different diseases. Research evaluating the effects of dietary cholesterol, often provided by eggs or as a component of Western-style diets, demonstrates that cholesterol-rich dietary patterns affect markers of immune inflammation and cellular cholesterol metabolism, while additionally modulating lipoprotein profiles and functional properties of HDL. Further, cholesterol-rich diets appear to differentially impact immunomodulatory lipid pathways across human populations of variable metabolic status, suggesting that these complex mechanisms may underlie the relationship between dietary cholesterol and immunity. Given the Dietary Guidelines for Americans 2015–2020 revision to no longer include limitations on dietary cholesterol, evaluation of dietary cholesterol recommendations beyond the context of cardiovascular disease risk is particularly timely. This review provides a comprehensive and comparative analysis of significant and controversial studies on the role of dietary cholesterol and lipid metabolism in the pathophysiology of infectious disease and autoimmune disorders, highlighting the need for further investigation in this developing area of research.

Cardiovascular disease (CVD) is the leading cause of death in the United States. For years, dietary cholesterol was implicated in increasing blood cholesterol levels leading to the elevated risk of CVD. To date, extensive research did not show evidence to support a role of dietary cholesterol in the development of CVD. As a result, the 2015–2020 Dietary Guidelines for Americans removed the recommendations of restricting dietary cholesterol to 300 mg/day. This review summarizes the current literature regarding dietary cholesterol intake and CVD. It is worth noting that most foods that are rich in cholesterol are also high in saturated fatty acids and thus may increase the risk of CVD due to the saturated fatty acid content. The exceptions are eggs and shrimp. Considering that eggs are affordable and nutrient-dense food items, containing high-quality protein with minimal saturated fatty acids (1.56 gm/egg) and are rich in several micronutrients including vitamins and minerals, it would be worthwhile to include eggs in moderation as a part of a healthy eating pattern. This recommendation is particularly relevant when individual’s intakes of nutrients are suboptimal, or with limited income and food access, and to help ensure dietary intake of sufficient nutrients in growing children and older adults.

Previous recommendations to limit dietary cholesterol intake have been eliminated for most adults. Questions remain about whether dietary cholesterol has adverse cardiovascular effects among individuals with impaired fasting glucose or diabetes (IFG/T2DM). We used data for 993 adults (40.9% female), ages 35&ndash, &lt, 65 years, with prevalent IFG/T2DM in the prospective Framingham Offspring Study to address this question. Dietary cholesterol was assessed using 3-day diet records at exams 3 and 5 and used to classify subjects into sex-specific tertiles of mean cholesterol intake. Outcomes included fasting lipid levels over 20 years and incident cardiovascular disease (CVD). Statistical analyses included repeated measures mixed regression models and Cox proportional hazards models to adjust for confounding. Among adults with T2DM/IFG, there was no consistent association between dietary cholesterol intake and fasting low-density lipoprotein (LDL), high-density lipoprotein (HDL), LDL/HDL ratio, or triglycerides over 20 years of follow-up. In longitudinal analyses, the adjusted hazard ratio for CVD in the highest (vs. lowest) sex-specific tertile of cholesterol intake was 0.61 (95% CI: 0.41, 0.90). These analyses provide no evidence of an adverse association between dietary cholesterol and serum lipid levels or atherosclerotic CVD risk among adults with prevalent IFG/T2DM.

Cholesterol is an essential molecule that exerts pleiotropic actions. Although its presence is vital to the cell, its excess can be harmful and, therefore, sustaining cholesterol homeostasis is crucial to maintaining proper cellular functioning. It is well documented that high plasma cholesterol concentration increases the risk of atherosclerotic heart disease. In the last decades, several studies have investigated the association of plasma cholesterol concentrations and the risk of cardiovascular diseases as well as the signaling pathways involved in cholesterol homeostasis. Here, we present an overview of several mechanisms involved in intestinal cholesterol absorption, the regulation of cholesterol synthesis and uptake. We also discuss the importance of reverse cholesterol transport and transintestinal cholesterol transport to maintain cholesterol homeostasis and prevent atherosclerosis development. Additionally, we discuss the influence of dietary cholesterol on plasma cholesterol concentration and the new recommendations for cholesterol intake in a context of a healthy dietary pattern.

In previous studies, it was demonstrated that lipid core nanoparticles (LDE) resemble the low-density lipoprotein structure and carrying the antiproliferative agent paclitaxel (PTX) strongly reduced atherosclerosis lesions induced in rabbits by cholesterol feeding. Currently, the aim was to verify whether combining LDE-PTX treatment with methotrexate (MTX) associated with LDE (LDE-MTX) could accelerate the atherosclerosis regression attained with single LDE-PTX treatment, after withdrawing the cholesterol feeding. Thirty-eight rabbits were fed 1% cholesterol chow for 8 weeks. Six of these rabbits were then euthanized for analyses of the aorta (controls). In the remaining rabbits, cholesterol feeding was withdrawn, and those 32 animals were allocated to 3 groups submitted to different 8-week intravenous treatments, all once/week: LDE-PTX (n = 10; 4 mg/kg), LDE-PTX + LDE-MTX (n = 11; 4 mg/kg), and LDE-alone (n = 11). Rabbits were then euthanized and aortas were excised for morphometric, immunohistochemical, and gene expression analyses. After cholesterol feeding withdrawal, in comparison with LDE-alone group, both LDE-PTX and LDE-PTX + LDE-MTX treatments had the ability to increase the regression of plaque areas: −49% in LDE-PTX and −59% for LDE-PTX + LDE-MTX. However, only LDE-PTX + LDE-MTX treatment elicited reduction in the intima area, estimated in −57%. Macrophage presence in aortic lesions was reduced 48% by LDE-PTX and 43% by LDE-PTX + LDE-MTX treatment. Matrix metalloproteinase 9 was reduced by either LDE-PTX (74%) or LDE-PTX + LDE-MTX (78%). Tumor necrosis factor α gene expression was reduced 65% by LDE-PTX and 79% by LDE-PTX + LDE-MTX. In conclusion, treatment with LDE-PTX indeed accelerated plaque reduction after cholesterol feeding; LDE-PTX + LDE-MTX further increased this effect, without any observed toxicity. These results pave the way for the use of combined chemotherapy to achieve stronger effects on aggravated, highly inflamed atherosclerotic lesions.

Evidence suggests that both high and low birth weight children have increased the risk for obesity and the metabolic syndrome in adulthood. Previously we have found altered feeding behaviour and food preferences in pre-school children and adults born with low birth weight. In this study, we investigated if birth weight was associated with different intake of fat, carbohydrate and/or protein at 6–12 years of age. This is a cross-sectional study where 255 guardians answered online and telephone questions including anthropometrics and demographic data, parental family food rules (food control, encouragement and restriction) and a complete web-based FFQ for their children (130 boys and 125 girls). Baseline demographic and parental food rules characteristics did not differ accordingly to sex. Linear regression models were conducted separately for each sex, adjusted for income, age and maternal age. There were no differences in total energy intake, but energy density (ED, energy content/g) was negatively associated with birth weight in boys. Macronutrient analysis showed that ED intake was from a greater intake of fat. Birth weight was not a significant predictor of protein and carbohydrate intake in boys. In girls, we saw a positive correlation between fat intake and cholesterol intakev. birth weight, but no association with ED intake (results did not remain after adjustment). The study shows that low birth weight is associated with altered fat intake in childhood in a sex-specific manner. It is likely that biological factors such as fetal programming of homoeostatic and/or hedonic pathways influencing food preferences are involved in this process.

There is a growing and alarming prevalence that increased serum cholesterol is closely related to increased cardiovascular disease risk. Probiotic consumption could be a safe and natural strategy to combat. Therefore, we sought to examine the cholesterol-lowering potential of co-supplementation of probiotic bacteria Lactobacillus fermentum MTCC: 5898-fermented buffalo milk (2.5% fat) in rats fed cholesterol-enriched diet. Male Wistar rats were divided into three groups on the basis of feed, viz. group 1, fed standard diet (SD); group 2, fed cholesterol-enriched diet (CED); and group 3, fed cholesterol-enriched diet along with L. fermentum MTCC: 5898-fermented milk (CED+LF) for 90 days. At the endpoint, significantly higher levels of serum total cholesterol, low-density lipoprotein cholesterol, triacylglycerols, very low density lipoprotein cholesterol, atherogenic index, coronary artery risk index, hepatic lipids, lipid peroxidation, and mRNA expression of inflammatory cytokines (TNF-α and IL-6) in the liver while significantly lower levels of serum high-density lipoprotein cholesterol and anti-oxidative enzyme activities, catalase, superoxide dismutase, and glutathione peroxidase in the liver and kidney were observed in the CED group compared to the SD group. Compared to the CED group, these adverse physiological alterations were found significantly improved in the CED+LF group. Hence, this study proposes that L. fermentum MTCC: 5898 is a potential probiotic bacteria that can be consumed to tackle hypercholesterolemia. Graphical Abstract ᅟ.

Background The liver X receptors ( LXRs ; α/β) are nuclear receptors known to regulate cholesterol homeostasis and the production of select hematopoietic populations. The objective of this study was to determine the importance of LXR s and a high‐fat high‐cholesterol diet on global hematopoiesis, with special emphasis on endothelial progenitor cells ( EPC s), a vasoreparative cell type that is derived from bone marrow hematopoietic stem cells. Methods and Results Wild‐type and LXR double‐knockout ( Lxr αβ −/− ) mice were fed a Western diet ( WD ) to increase plasma cholesterol levels. In WD ‐fed Lxr αβ −/− mice, flow cytometry and complete blood cell counts revealed that hematopoietic stem cells, a myeloid progenitor, and mature circulating myeloid cells were increased; EPC numbers were significantly decreased. Hematopoietic stem cells from WD ‐fed Lxr αβ −/− mice showed increased cholesterol content, along with increased myeloid colony formation compared with chow‐fed mice. In contrast, EPC s from WD ‐fed Lxr αβ −/− mice also demonstrated increased cellular cholesterol content that was associated with greater expression of the endothelial lineage markers Cd144 and Vegfr2 , suggesting accelerated differentiation of the EPC s. Treatment of human umbilical vein endothelial cells with conditioned medium collected from these EPC s increased THP ‐1 monocyte adhesion. Increased monocyte adhesion to conditioned medium–treated endothelial cells was recapitulated with conditioned medium from Lxr αβ −/− EPC s treated with cholesterol ex vivo, suggesting cholesterol is the main component of the WD inducing EPC dysfunction. Conclusions LXR s are crucial for maintaining the balance of hematopoietic cells in a hypercholesterolemic environment and for mitigating the negative effects of cholesterol on EPC differentiation/secretome changes that promote monocyte‐endothelial adhesion.

Amyloid‐β (Aβ) peptides, the major constituent of plaques, are generated by sequential proteolytic cleavage of the amyloid precursor protein (APP) via β‐secretase (BACE1) and the γ‐secretase complex. It has been proposed that the abnormal secretion and accumulation of Aβ are the initial causative events in the development of Alzheimer's disease (AD). Drugs modulating this pathway could be used for AD treatment. Previous studies indicated that carbon monoxide (CO), a product of heme oxygenase (HO)‐1, protects against Aβ‐induced toxicity and promotes neuroprotection. However, the mechanism underlying the mitigative effect of CO on Aβ levels and BACE1 expression is unclear. Here, we show that CO modulates cleavage of APP and Aβ production by decreasing BACE1 expression in vivo and in vitro. CO reduces Aβ levels and improves memory deficits in AD transgenic mice. The regulation of BACE1 expression by CO is dependent on nuclear factor‐kappa B (NF‐κB). Consistent with the negative role of SIRT1 in the NF‐κB activity, CO fails to evoke significant decrease in BACE1 expression in the presence of the SIRT1 inhibitor. Furthermore, CO attenuates elevation of BACE1 level in brains of 3xTg‐AD mouse model as well as mice fed high‐fat, high‐cholesterol diets. CO reduces the NF‐κB‐mediated transcription of BACE1 induced by the cholesterol oxidation product 27‐hydroxycholesterol or hydrogen peroxide. These data suggest that CO reduces the NF‐κB‐mediated BACE1 transcription and consequently decreases Aβ production. Our study provides novel mechanisms by which CO reduces BACE1 expression and Aβ production and may be an effective agent for AD treatment.

The authors analyzed the difference in weight gain and nutrition, according to the BMI before pregnancy. They divided 91 subjects into BMI group I (normal weight) and BMI group 2 (overweight) before pregnancy. In general, the BMI before pregnancy did not influence weight gain but, in the BMI group 2, the intakes of all of cholesterol, total fatty acids, vitamin B 12, iron, and copper were significantly higher. Neither group exhibited sufficient intake of vitamin B 1, vitamin B2, niacin, vitamin B6, folic acid, calcium, magnesium, iron, or zinc. Pre-pregnancy weight management and nutrition during pregnancy is very important.

A phenocopy is an environmentally-defined phenotype that mimics another, genetically-determined phenotype. The severity of hypercholesterolaemia, extent of down regulation of LDL receptor expression and aortic root localisation of atherosclerosis in cholesterol-fed rabbits strikingly resemble the cardinal features of homozygous familial hypercholesterolaemia (FH) in humans, suggesting that the former is a phenocopy of the latter. This review compares the metabolic and pathological consequences of induced hypercholesterolaemia in rabbits with those of homozygous FH and contrasts their ease of reversibility on resumption of a normal diet with the refractoriness to lipid-lowering therapy of homozygotes, in whom major adverse cardiovascular events and survival depend upon the prevailing level of serum cholesterol. The monofactorial nature of the atherosclerosis in both situations corroborates Anitschkow's concept that "Cholesterin ist alles." In contrast, atherosclerosis in heterozygous FH differs in several respects from that of homozygotes, notably the lack of aortic root involvement and in its multifactorial aetiology, with raised LDL cholesterol, male gender, low HDL cholesterol and raised lipoprotein (a) all contributing to its clinical expression. In angiographic trials of LDL-lowering therapy regression of coronary lesions was observed in FH heterozygotes whereas they progressed in non-FH subjects. Similarly, carotid artery plaques progressed less in FH heterozygotes than in non-FH subjects, in both instances despite FH patients having higher LDL cholesterol levels on treatment. These findings suggest that, compared with non-FH subjects, atherosclerotic lesions in FH heterozygotes may be hyper-responsive to LDL-lowering therapy, whereas treatment of homozygous FH remains a major challenge.

Rabbits are a suitable animal model for atherosclerosis due to their sensitivity to dietary cholesterol. Moreover, rabbits have lipoprotein profiles that are more similar to humans than those of other laboratory animals. However, little is known about the transcriptomic information related to atherosclerosis in rabbits. We aimed to determine the changes in the livers of rabbits fed a normal chow diet (control) or high cholesterol diet (HCD) by histological examinations and RNA sequencing analysis. Compared with the control group, the lipid levels and small LDL subfractions in plasma were increased, and aortic atherosclerotic plaques were formed in the HCD group. Most importantly, HCD resulted in lipid accumulation and inflammation in the livers. Transcriptomic analysis of the liver showed that HCD induces 1183 differentially expressed genes (DEGs) that mainly participate in the regulation of inflammation and lipid metabolism. Furthermore, the signaling pathways involved in inflammation and lipid metabolism were enriched by KEGG pathway analysis. In addition, hepatic DEGs of the HCD group were further validated by real-time PCR. These results suggest that HCD causes liver lipid accumulation and inflammatory response. Although the relationships between these hepatic changes and atherogenesis need further investigation, these findings provide a fundamental framework for future research on human atherosclerosis using rabbit models.

Ethanolic extract of leaves of Morus alba L. (M. alba), known as white mulberry, was orally administered (100 mg/kg b.wt) for 8 weeks to female Wistar rats that were fed a high-cholesterol diet (HCD), to investigate the potential of M. alba leaves in attenuation of obesity, dyslipidemia, insulin resistance, and deficits in mood, cognitive as well as motor activity that are linked to the adipokines secretions of visceral adipose tissue. Results showed that M. alba diminished body weight gain, hypercholesterolemia, hypertriglyceridemia, atherogenic (AI) & coronary artery indices (CRI), and ameliorated glucose level and insulin resistance index in rats on HCD, compared with untreated HCD rats. Moreover, M. alba administration significantly decreased serum leptin and resistin contents as well as their mRNA expression in visceral adipose tissue, but significantly increased serum adiponectin level, and its mRNA expression in visceral adipose tissue in rats fed on HCD, compared to those in untreated HCD group. Regarding behavioral alterations, M. alba attenuated motor deficit, declined memory, depression and anxiety-like behavior, as well in rats on HCD, compared to that noticed in untreated HCD rats. The current data showed that serum leptin and resistin showed a positive correlation with and body weight gain, triglycerides (TG), AI as well as CRI, but showed a negative correlation with exploration, declined memory, depression- and anxiety-like behavior. Conversely, serum adiponectin showed a negative correlation with and body weight gain, TG, AI as well as CRI, but showed a positive correlation with locomotor activity, exploration, declined memory, and depression- and anxiety-like behavior. In conclusion, M. alba leaves supplementation could attenuate adiposity, insulin resistance behavioral deficits via down-regulation of regulation of gene expression of leptin, resistin, but up-regulation of adiponectin gene expression in the visceral adipose tissue of rats fed a high-cholesterol diet.

High levels of plasma high-density lipoprotein-cholesterol (HDL-C) are inversely associated with the risk of atherosclerosis and other cardiovascular diseases; thus, pharmacological inhibition of cholesteryl ester transfer protein (CETP) is considered to be a therapeutic method of raising HDL-C levels. However, many CETP inhibitors have failed to achieve a clinical benefit despite raising HDL-C. In the study, we generated transgenic (Tg) rabbits that overexpressed the human CETP gene to examine the influence of CETP on the development of atherosclerosis. Both Tg rabbits and their non-Tg littermates were fed a high cholesterol diet for 16 weeks. Plasma lipids and body weight were measured every 4 weeks. Gross lesion areas of the aortic atherosclerosis along with lesional cellular components were quantitatively analyzed. Overexpression of human CETP did not significantly alter the gross atherosclerotic lesion area, but the number of macrophages in lesions was significantly increased. Overexpression of human CETP did not change the plasma levels of total cholesterol or low-density lipoprotein cholesterol but lowered plasma HDL-C and increased triglycerides. These data revealed that human CETP may play an important role in the development of atherosclerosis mainly by decreasing HDL-C levels and increasing the accumulation of macrophage-derived foam cells.

The effect of the addition of galactooligosaccharides (GOS) on sterol bioaccessibility in three plant sterol (PS)-enriched milk-based fruit beverages (without GOS addition (MfB) and with 2.5 g (MfB-G2) and 5.0 g (MfB-G5) GOS per 250 mL) was evaluated after micellar gastrointestinal digestion. Cholesterol bioaccessibility was very similar among beverages, though a slight significant increase (from 80% to 85%) was observed by the addition of 5.0 g GOS. The addition of GOS did not affect total PS bioaccessibility (≈37%). Based on the results obtained after micellar digestion, it has been demonstrated that these beverages could be a suitable food matrix for simultaneous enrichment with PS and GOS. The harmonized in vitro digestion model INFOGEST was applied to the MfB beverage, but the cholesterol content could not be quantified due to its contribution of bile salts. Hence, it was proposed: (i) a change in porcine bile salt concentration from 10 mM to 1.4 mM (in order to compare with micellar digestion); or (ii) a change of bile salt origin (bovine instead of porcine), maintaining physiological concentration (10 mM, INFOGEST condition). Both options allowed cholesterol quantification, with bioaccessibilities of 62% (reduction of bile salts) and 38% (replacement of the bile salt source), whereas plant sterol bioaccessibilities were 22% and 14%, respectively. Therefore, the change of bile salt origin maintaining INFOGEST concentration is proposed as a method to evaluate sterol (cholesterol and PS) bioaccessibility in these beverages, demonstrating the need for the selection of appropriate conditions of the INFOGEST harmonized method according to the food matrix and compounds to be determined.

The effects of cinnamaldehyde (CIN), a commonly consumed food flavor, against high-cholesterol diet (HCD)-induced vascular damage in rabbits were evaluated. Male New Zealand rabbits (n = 24) were allocated to four groups at random: control, fed with standard rabbit chow; CIN, fed with standard diet and administered CIN; HCD, fed with 1% cholesterol-enriched diet; and HCD-CIN, fed with HCD and treated with CIN. CIN was orally given at a dose of (10 mg/kg/day) concomitantly with each diet type from day 1 until the termination of the experimental protocol (4 weeks). HCD elicited significant elevations in serum levels of total cholesterol (TC), triglycerides (TGs), and high- and low-density lipoprotein cholesterol (HDL-C and LDL-C, respectively) compared with control rabbits. Moreover, aortic levels of nitric oxide metabolites (NOx) and antioxidant enzyme activities were significantly lower, while aortic levels of malondialdehyde (MDA) and myeloperoxidase (MPO) activity were significantly higher, in HCD-fed rabbits relative to control animals. CIN administration mitigated or completely reversed HCD-induced metabolic alterations, vascular oxidative stress, and inflammation. Moreover, CIN ameliorated HCD-induced vascular functional and structural irregularities. Aortic rings from HCD-CIN group showed improved relaxation to acetylcholine compared to aortas from HCD group. Moreover, CIN decreased atherosclerotic lipid deposition and intima/media (I/M) ratio of HCD aortas. CIN-mediated effects might be related to its ability to attenuate the elevated aortic mRNA expression of cholesteryl ester transfer protein (CETP) and MPO in HCD group. Interestingly, the vasculoprotective effects of CIN treatment in the current study do not seem to be mediated via Nrf2-dependent mechanisms. In conclusion, CIN may mitigate the development of atherosclerosis in hypercholestrolemic rabbits via cholesterol-lowering, antiinflammatory and antioxidant activities.