Decreased Plasma Cholesterol Research Articles

Bacterial Fermentation of Water-Soluble Cellulose Acetate Raises Large-Bowel Acetate and Propionate and Decreases Plasma Cholesterol Concentrations in Rats.

We hypothesized that water-soluble cellulose acetate (WSCA) could be useful tool for the delivery of short-chain fatty acids to the large intestine. Rats were fed a control diet or a diet containing graded levels of WSCA for up to 21 days. Consuming WSCA dose-dependently increased large-bowel acetate and propionate concentrations through the bacterial fermentation. When WSCA was used as substrate, acetyl esterase activity in the cecal bacteria was detected solely in rats fed WSCA, in which the activity increased over time accompanied by an increased number of Bacteroides xylanisolvens. Consuming WSCA at a 4% level increased the goblet cell numbers and mucin contents in the cecum and lowered plasma cholesterol concentrations, which tended to correlate with the portal plasma concentrations of propionate. The results suggest that bacterial fermentation of WSCA is characterized by the greater production of acetate and propionate, which may contribute to the physiologic alterations.

Suppression of abdominal fat and anti-hyperlipidemic potential of Emblica officinalis: Upregulation of PPARs and identification of active moiety.

Since ancient time, Emblica officinalis (E. officinalis) is being used for the management of various ailments. Phytochemical analysis proves that fruit juice of E. officinalis contains high amount gallic acid, which could be responsible for medicinal potentials. Hence in this study, gallic acid and fruit juice of E. officinalis were evaluated for anti-hyperlipidemic potential in various experimental animal models. Experimentally, hyperlipidemia was induced through administration of poloxamer-407, tyloxapol and high-fat-diet supplement in rats. Treatment with gallic acid as well as fruit juice of E. officinalis decreased plasma cholesterol and reduced oil infiltration in liver and aorta. Mechanistically, E. officinalis increased peroxisome proliferator-activated receptors-α (PPARα) expression and increased activity of lipid oxidation through carnitine palmitoyl transferase (CPT) along with decreased activity of hepatic lipogenic enzymes i.e. glucose-6-phosphate dehydrogenase (G6PD), fatty acid synthase (FAS) and malic enzyme (ME). Additionally, E. officinalis increased cholesterol uptake through increased LDL-receptor expressions on hepatocytes and decreased LDL-receptor degradation due to decreased proprotein convertase subtilisin/kexin type 9 (PCSK9) expression. Simultaneously, E. officinalis showed ability to restore glucose homeostasis through increased Glut4 and PPARγ protein expression in adipose tissue. These findings exposed central role of gallic acid in E. officinalis arbitrated anti-hyperlipidemic action through upregulation of PPARs, Glut4 and lipogenic enzymes, and decreased expression of PCSK9 and lipogenic enzymes. Findings from this experiment demonstrated that E. officinalis is a potential therapy for management of hyperlipidemia and gallic acid could be a potential lead candidate.

EFFECT OF USING DIFFERENT LEVELS OF MORINGA OLEIFERA MEAL IN THE DIETS OF JAPANESE QUAILS ON THEIR PRODUCTIVE PERFORMANCE

The aim of this study was to inspect the effect of feeding Japanese quail chicks on diets containing different levels of Moringa Oleifera meal (MOM) on productive performance, carcass quality and blood constituents. Six hundred unsexed one- week-old birds of Japanese quail were equally divided into five experimental groups of 120 birds each. They were fed at 0, 5, 10, 15 and 20% with MOM. The experiment lasted for six weeks during which the effect of MOM on the body weight, feed consumption, feed conversion, blood constituents and carcass traits were observed as indicator of performance. The results showed that, birds fed on 5 % MOM gained significantly higher body weight and body weight gain than birds fed the control diet, but the lowest feed consumption (P≤0.01) and best feed conversion ratio were obtained by using 20% MOM compared to control group. Using 20% MOM increased the weight of heart and liver significantly (P≤0.05) than other groups, but there were no significantly (P>0.05) differences in gizzard, carcass and edible parts weights of the growing Japanese quails in the four treatments. Plasma total protein and albumin were significantly higher in two groups (15 and 20 %) MOM as compared to other treated groups or control group. The best level of MOM was 20% which recorded a decrease in plasma cholesterol and LDL compared to control group, but plasma AST and ALT decreased with all levels of MOM. This study indicate that the 20% MOM diet can improve quail performance without negative effects on growth and carcass traits.

Impact of n-3 Docosapentaenoic Acid Supplementation on Fatty Acid Composition in Rat Differs Depending upon Tissues and Is Influenced by the Presence of Dairy Lipids in the Diet.

The n-3 docosapentaenoic acid (n-3 DPA) could be a novel source of n-3 long-chain polyunsaturated fatty acids (LCPUFA) with beneficial physiological effects. Following the supplementation of 0.5% purified n-3 DPA for 3 weeks from weaning, the n-3 DPA content increased in one-half of the 18 studied tissues (from +50% to +110%, p < 0.05) and mostly affected the spleen, lung, heart, liver, and bone marrow. The n-3 DPA was slightly converted into DHA (+20% in affected tissues, p < 0.05) and mostly retroconverted into EPA (35-46% of n-3 DPA intake in liver and kidney) showing an increased content of these LCPUFA in specific tissues. The partial incorporation of dairy lipids in the diet for 6 weeks increased overall n-3 PUFA status and brain DHA status. Furthermore, the n-3 DPA supplementation and dairy lipids had an additive effect on the increase of n-3 PUFA tissue contents. Moreover, n-3 DPA supplementation decreased plasma cholesterol.

Genetic Risk Stratification: Tipping Point for Global Primary Prevention of Coronary Artery Disease.

In 2003, Wald and Law1 predicted that coronary artery disease (CAD) would be markedly attenuated if not eliminated. CAD is a preventable disease based on randomized, placebo-controlled clinical trials that consistently showed 30% to 40% reduction in cardiac events with decreased plasma cholesterol.1 Epidemiologists claimed for decades that 40% to 50% of predisposition for CAD is genetic. Discovery of the first genetic risk variant in 2007 has led to an avalanche of >90 genetic risk variants predisposing to CAD, each of genome-wide significance and replicated in independent populations,2 but each with relatively low individual effect sizes. The total individual genetic risk burden for CAD is proportional to the number of genetic risk variants inherited. These variants account for ≈25% of genetic predisposition to CAD, which is less than the predicted 40%, signaling that more genetic risk variants are yet to be discovered. It is interesting to note that only one third of the genetic risk variants for CAD mediate their risk through known conventional risk factors. Exploration of the unknown pathways mediating the risk conferred by these genetic variants is already enabling new insights into the pathogenesis of coronary atherosclerosis (eg, inflammation, lack of protection of high-density lipoprotein cholesterol) and novel targets for the development of specific drugs. A major impetus for our pursuit of genetic risk variants was to better predict those at higher risk for CAD who would benefit most from preventive measures, particularly primary prevention. The genetic …

The BCR-ABL1 Inhibitors Imatinib and Ponatinib Decrease Plasma Cholesterol and Atherosclerosis, and Nilotinib and Ponatinib Activate Coagulation in a Translational Mouse Model.

Treatment with the second and third generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) increases cardiovascular risk in chronic myeloid leukemia (CML) patients. We investigated the vascular adverse effects of three generations of TKIs in a translational model for atherosclerosis, the APOE*3Leiden.CETP mouse. Mice were treated for sixteen weeks with imatinib (150 mg/kg BID), nilotinib (10 and 30 mg/kg QD) or ponatinib (3 and 10 mg/kg QD), giving similar drug exposures as in CML-patients. Cardiovascular risk factors were analyzed longitudinally, and histopathological analysis of atherosclerosis and transcriptome analysis of the liver was performed. Imatinib and ponatinib decreased plasma cholesterol (imatinib, −69%, p < 0.001; ponatinib 3 mg/kg, −37%, p < 0.001; ponatinib 10 mg/kg−44%, p < 0.001) and atherosclerotic lesion area (imatinib, −78%, p < 0.001; ponatinib 3 mg/kg, −52%, p = 0.002; ponatinib 10 mg/kg, −48%, p = 0.006), which were not affected by nilotinib. In addition, imatinib increased plaque stability. Gene expression and pathway analysis demonstrated that ponatinib enhanced the mRNA expression of coagulation factors of both the contact activation (intrinsic) and tissue factor (extrinsic) pathways. In line with this, ponatinib enhanced plasma levels of FVII, whereas nilotinib increased plasma FVIIa activity. While imatinib showed a beneficial cardiovascular risk profile, nilotinib and ponatinib increased the cardiovascular risk through induction of a pro-thrombotic state.

Abstract 210: Beta-carotene Conversion to Vitamin a Delays Atherosclerosis Progression and Accelerates Atherosclerosis Regression

β-carotene (BC) from plants is strong antioxidant and is the precursor of vitamin A in animals. Human studies show that elevated BC blood levels correlate with lower incidence of heart disease, but the molecular mechanisms are unclear. While humans accumulate high amounts of BC in blood, rodents completely metabolize BC to vitamin A, precluding the possibility of studying if BC influences heart disease using mouse models. To overcome this, we used a mouse model lacking the enzyme that converts BC to vitamin A (BC oxygenase 1, BCO1) and studied if BC plays a role in atherosclerosis, the main cause of heart disease. We first crossed Bco1 -/- mice with Ldlr -/- mice to generate Bco1 -/- / Ldlr -/- mice. These mice were fed Western diet (WD) containing BC (WD-BC) for 12 wks, accumulated levels of BC in blood comparable to those observed in humans (12±2 μM), as well as in atherosclerotic lesions, while Ldlr -/- mice fed WD-BC only accumulated trace amounts of BC in blood (0.3±0.1 μM). Ldlr -/- mice fed WD-BC showed delayed atherosclerosis progression (40% reduction in plaque size, n=10-12 mice/group) when compared to those fed WD without BC (WD-noBC). These changes were accompanied by decreased plasma cholesterol (35%) and triglyceride (~55%) levels (n=10-12 mice/group). People typically present for treatment of atherosclerotic disease after plaques have advanced. Thus, we next tested whether BC plays a role in atherosclerosis regression after lipid lowering. For this purpose, we utilized a LDLR antisense oligonucleotide (LDLR-ASO) strategy to block expression of the LDLR to induce hypercholesterolemia. Wild-type and Bco1 -/- mice were fed WD-noBC and simultaneously treated with LDLR-ASO for 16 wks. After LDLR-ASO treatment was stopped, plasma cholesterol levels fell from 700mg/mL to 70mg/mL. Mice were also switched to WD-BC or continued with WD-noBC for 3 wks. Wild-type mice, but not Bco1 -/- mice, fed WD-BC showed a reduced content of plaque macrophages (30%) and newly recruited monocytes (25%) (n=7 to 12 mice/group) when compared to those fed WD-noBC. We are currently in the process of elucidating the molecular mechanisms responsible of these beneficial effects of BC on atherosclerosis progression and regression.

Non-Native Conformational Isomers of the Catalytic Domain of PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels.

PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases plasma cholesterol levels by promoting LDL receptor degradation. Current antibody inhibitors block the interaction between PCSK9 and LDL receptors, significantly decrease plasma cholesterol levels, and provide beneficial clinical outcomes. To reduce the action of PCSK9 in plasma, a novel strategy that will produce a panel of non-native, conformationally-altered isomers of PCSK9 (X-PCSK9) to develop active immunotherapy targeting of native PCSK9 and inhibiting/blocking the interaction of PCSK9 with LDL receptor, thus decreasing plasma cholesterol levels is proposed. The authors used the scrambled disulfide bond technique to generate conformationally-altered isomers of the catalytic domain of mouse PCSK9. The focus was on the immune response of four X-isomers and their effects on plasma cholesterol and triglyceride levels in both C57BL/6J and Apoe−/− mice. The authors showed that the four immunogens produced significant immunogenicity against native PCSK9 to day 120 after immunization of C57BL/6J and Apoe−/− mice. This resulted in significantly decreased plasma cholesterol levels in C57BL/6J mice, and to a lesser degree in Apoe−/− mice. The X-PCSK9-B1 treated mice had increased LDL receptor mRNA and protein levels at day 120 after treatment. Thus, this study provides a new, potentially promising approach that uses long-term immunotherapy for a treatment of hypercholesterolemia.

Bempedoic Acid Lowers Low-Density Lipoprotein Cholesterol and Attenuates Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient (LDLR+/- and LDLR-/-) Yucatan Miniature Pigs.

Bempedoic acid (BemA; ETC-1002) is a novel drug that targets hepatic ATP-citrate lyase to reduce cholesterol biosynthesis. In phase 2 studies, BemA lowers elevated low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients. In the present study, we tested the ability of BemA to decrease plasma cholesterol and LDL-C and attenuate atherosclerosis in a large animal model of familial hypercholesterolemia. Gene targeting has been used to generate Yucatan miniature pigs heterozygous (LDLR+/-) or homozygous (LDLR-/-) for LDL receptor deficiency (ExeGen). LDLR+/- and LDLR-/- pigs were fed a high-fat, cholesterol-containing diet (34% kcal fat; 0.2% cholesterol) and orally administered placebo or BemA for 160 days. In LDLR+/- pigs, compared with placebo, BemA decreased plasma cholesterol and LDL-C up to 40% and 61%, respectively. In LDLR-/- pigs, in which plasma cholesterol and LDL-C were 5-fold higher than in LDLR+/- pigs, BemA decreased plasma cholesterol and LDL-C up to 27% and 29%, respectively. Plasma levels of triglycerides and high-density lipoprotein cholesterol, fasting glucose and insulin, and liver lipids were unaffected by treatment in either genotype. In the aorta of LDLR+/- pigs, BemA robustly attenuated en face raised lesion area (-58%) and left anterior descending coronary artery cross-sectional lesion area (-40%). In LDLR-/- pigs, in which lesions were substantially more advanced, BemA decreased aortic lesion area (-47%) and left anterior descending coronary artery lesion area (-48%). In a large animal model of LDLR deficiency and atherosclerosis, long-term treatment with BemA reduces LDL-C and attenuates the development of aortic and coronary atherosclerosis in both LDLR+/- and LDLR-/- miniature pigs.

Sterol 27-hydroxylase gene dosage and the antiatherosclerotic effect of Rifampicin in mice.

Sterol 27-hydroxylase (CYP27A1) catalyzes the hydroxylation of cholesterol to 27-hydroxycholesterol (27-OHC) and regulates cholesterol homeostasis. In Cyp27a1/ Apolipoprotein E (ApoE) double knockout (KO) mice fed with Western diet (WD), the atherosclerotic phenotype found in ApoE KO mice was reversed. As protective mechanism, up-regulation of Cyp3a11 and Cyp7a1 was proposed. Cyp27a1 heterozygote/ApoE KO (het) mice, with reduced Cyp27a1 expression and normal levels of Cyp7a1 and Cyp3a11, developed more severe lesions than ApoE KO mice. To analyze the contribution of Cyp3a11 to the protection of atherosclerosis development, Cyp3a11 was induced by Rifampicin (RIF) in ApoE KO and het mice. Males were fed with WD and treated daily with RIF (10 mg/kg ip) or vehicle for 4 weeks. Atherosclerosis was quantified in the aortic valve. Plasma lipids and 27-hydroxycholesterol (27-OHC), expression of cytochromes P450 and genes involved in cholesterol transport and bile acids (BAs) signaling in liver and intestine, and intestinal cholesterol absorption were analyzed. RIF increased expression of hepatic but not intestinal Cyp3a11 4-fold in both genotypes. In ApoE KO mice treated with RIF, we found a 2-fold decrease in plasma cholesterol, and a 2-fold increase in high-density lipoprotein/low-density lipoprotein ratio and CY27A1 activity. Intestinal cholesterol absorption remained unchanged and atherosclerotic lesions decreased approximately 3-fold. In het mice, RIF had no effect on plasma lipids composition, CYP27A1 activity, and atherosclerotic plaque development, despite a reduction in cholesterol absorption. In conclusion, the antiatherogenic effect of Cyp3a11 induction by RIF was also dependent on Cyp27a1 expression.

The role of Tripterygium wilfordii extract in weight loss, energy expenditure, glucose and lipid metabolism

Summary. Introduction: Obesity is a chronic disease that characterized by the disturbance of the body composition, which is expressed as the relative or absolute increase in the amount of adipose tissue. Tripterygium wilfordii is an herbaceous plant of the Celastraceae family which is widely used in China. The roots of this plant have many therapeutic properties. Recently in animal studies, it has been shown that Celastrol in the root of Tripterygum wilfordii has been associated with weight loss, suppression of food intake, and increased leptin sensitivity. Triptolide is another effective ingredient in this plant, has significantly reduced TG, TC, LDL-C and weight loss in animal models. Also, Celastrol has an anti-obesity effect in ob/ob mice, which reduces the intake of food and the percentage of body fat. Materials and methods: Searching for articles based on Electronic databases including Google Scholar (scholar.google.com), Pub Med (www.ncbi.nlm.nih.gov/pubmed), (Science Direct (, and Springer (www.springer.com) until November 2017. Results: The use of celastrol significantly reduces dietary intake and body mass in mice. Celastrol increased the energy expenditure (EE) and reduced the amount of respiratory exchange ratio (RER) in the mice. celastrol caused a very marked decrease in plasma cholesterol, triglyceride and LDL levels, as well as a significant increase in plasma HDL levels. also, triptolide reduces serum cholesterol, TG and LDL. Discussion: It Can be considered, Tripterygium wilfordii roots may be consumed as a therapeutic compound that prevents obesity and complications associated with this disease.

Effect of Sargassum wightii on Growth, Carcass and Serum Qualities of Broiler Chickens

The basic feed supplemented with Sargassum powder (1%, 2%, 3% and 4%) provided more amount of essential amino acids, long chain fatty acids and minerals necessary for the growth of poultry than the basic feed. The growth promoting ability of Sargassum increased from 1% to 2% and then there was ste ady state, which is reflected in the weight gain, feed intake, feed conversion rate, carcass qualities and serum parameters of poultry. Sargassum powder had increased the growth to gain about 1265g more weight compared to the control and the supplementing effect was the maximum at 2% Sargassum powder. The feed intake per bird increased from 4647g at 1% Sargassum powder to 4813g at 4% Sargassum powder while it was 3042g in the control group. The feed conversion rate increased from 51.5 to 51.8 instead of 33. 9% in the control. Sargassum treatment increased the liver weight from 2.26% to 2.30%, the heart weight from 0.53% - 0,45%, the gizzard from 1.76% to 1.83%, the intestinal weight from 210.2 to 226.18%, the leg proportion from 3.77% to 4.57%, the breast weigh t from 28.26% to 30.27%, the thigh weight from 13.37% to 14.68%, the drumstick from 14.16% to 15.28% and the dressing from 70.32% to 81.12%. The maximum supplementary effect was noted at 1% and 2% of the Sargassum powder. Dietary treatment of broiler chick s with Sargassum powder significantly (P&lt;0.05) decreased plasma cholesterol and globulin while increased the total serum protein, albumin, calcium, phosphorus and triglyceride compared to control. The 1% Sargassum gave 1.8 fold profits while 2%, 3% and 4% Sargassum powder gave 1.95 fold profit compared to the control. Meat qualities of chicks fed with 1% and 2% Sargassum were superior to the meat of poultry fed only with the basic feed.

Abnormal liver phosphatidylcholine synthesis revealed in patients with acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is associated with a severe pro-inflammatory response; although decreased plasma cholesterol concentration has been linked to systemic inflammation, any association of phospholipid metabolic pathways with ARDS has not been characterized. Plasma phosphatidylcholine (PC), the major phospholipid of circulating lipoproteins, is synthesized in human liver by two biologically diverse pathways: the cytidine diphosphocholine (CDP):choline and phosphatidylethanolamine N-methyltransferase (PEMT) pathways. Here, we used ESI-MS/MS both to characterize plasma PC compositions and to quantify metabolic fluxes of both pathways using stable isotopes in patients with severe ARDS and in healthy controls. Direct incorporation of methyl-D9-choline estimated CDP:choline pathway flux, while PEMT flux was determined from incorporations of one and two methyl-D3 groups derived from methyl-D9-choline. The results of MS/MS analysis showed significant alterations in plasma PC composition in patients with ARDS versus healthy controls. In particular, the increased overall methyl-D9-PC enrichment and, most importantly, the much lower methyl-D3-PC and methyl-D6-PC enrichments suggest increased flux through the CDP:choline pathway and reduced flux through the PEMT pathway in ARDS. To our knowledge, this study is the first to demonstrate significant plasma PC molecular compositional changes combined with associated alterations in the dynamics of PC synthetic pathways in patients with ARDS.

Structure-Specific Effects of Short-Chain Fatty Acids on Plasma Cholesterol Concentration in Male Syrian Hamsters.

Previous studies have shown that short-chain fatty acids (SCFAs) are capable of decreasing plasma cholesterol. However, the relative plasma-cholesterol-lowering activity of individual SCFAs and the underlying mechanisms by which SCFAs decrease plasma cholesterol remain largely unknown. The present study was done to compare the plasma-cholesterol-lowering potencies of four common SCFAs with 2-5 carbons and to investigate their interactions with gene expressions of key regulatory factors involved in cholesterol metabolism. For 6 weeks, five groups of male Golden hamsters were fed either a control high-cholesterol diet (HCD) or one of the four experimental HCDs containing 0.5 mol of acetate (Ac), propionate (Pr), butyrate (Bu), or valerate (Va) per kilogram of the diet. The results showed that Ac, Pr, and Bu significantly reduced plasma total cholesterol (TC) by 24, 18, and 17% (P < 0.05), respectively. All four SCFAs could decrease non-HDL cholesterol (non-HDL-C) and the non-HDL-C/HDL-C ratio. The addition of Ac, Pr, or Bu into the diet significantly promoted fecal excretion of bile acids by 121, 113, or 120% (P < 0.05), respectively, and upregulated the gene expressions of sterol-regulatory-element-binding protein 2 (SREBP2), low-density-lipoprotein receptor (LDLR), and cholesterol 7α-hydroxylase (CYP7A1) in the liver. It was concluded that SCFAs with 2-4 carbons (Ac, Pr, and Bu) are more hypocholesterolemic than Va, which has 5 carbons, via enhancing fecal excretion of bile acids and promoting the hepatic uptake of cholesterol from the blood.

Black Grass Jelly (Mesona Palustris Bl) Effervescent Powder has Anti-Dyslipidemia in High Cholesterol Diet-Fed Rats and Antioxidant Activity

Dyslipidemia that could be affected by hypercholesterol diet is a contributing factor in millions of deaths worldwide and a risk factor for ischemic heart disease and stroke. High soluble fiber diet is used as one of the non-pharmacological treatments to control hypercholesterolemia. Black Grass Jelly (Mesona palustris BL) also known as black cincau has a high soluble fiber content. This study aimed to investigate the effect of black cincau as effervescent powder form (BCEP) for anti-dyslipidemia and also the antioxidant activity. BCEP was orally administered to twenty male dyslipidemia Wistar rats induced with hypercholesterol diet for 3 weeks then plasma lipid profile was measured using enzymatic CHOD-PAP assay. The antioxidant activity also has been identified. Oral administration of 3 different doses of BCEP resulted in lipid profiles by decreasing plasma cholesterol (TC), triacylglycerol (TG), low-density lipoprotein (LDL), and also high-density lipoprotein (HDL) in dyslipidemia rats (α = 0.01). The increasing doses of BCEP revealed that it has a potential effect of decreasing plasma lipid.

Global inactivation of carboxylesterase 1 (Ces1/Ces1g) protects against atherosclerosis in Ldlr\u2212/\u2212 mice

Atherosclerotic cardiovascular disease is a leading cause of death in the western world. Increased plasma triglyceride and cholesterol levels are major risk factors for this disease. Carboxylesterase 1 (Ces1/Ces1g) has been shown to play a role in metabolic control. So far, the role of mouse Ces1/Ces1g deficiency in atherosclerosis is not elucidated. We generated Ces1/Ces1g−/− mice. Compared to wild-type mice, Ces1/Ces1g−/− mice had reduced plasma cholesterol levels. We then generated Ces1g−/−Ldlr−/− double knockout (DKO) mice, which were fed a Western diet for 16 weeks. Compared to Ldlr−/− mice, DKO mice displayed decreased plasma cholesterol and TG levels and reduced atherosclerotic lesions. Interestingly, knockdown of hepatic Ces1/Ces1g in Apoe−/− mice resulted in hyperlipidemia and exacerbated Western diet-induced atherogenesis. Mechanistically, global inactivation of Ces1/Ces1g inhibited intestinal cholesterol and fat absorption and Niemann-Pick C1 like 1 expression, and increased macrophage cholesterol efflux by inducing ATP-binding cassette subfamily A member 1 (ABCA1) and ABCG1. Ces1/Ces1g ablation also promoted M2 macrophage polarization and induced hepatic cholesterol 7α-hydroxylase and sterol 12α-hydroxylase expression. In conclusion, global loss of Ces1/Ces1g protects against the development of atherosclerosis by inhibiting intestinal cholesterol and triglyceride absorption and promoting macrophage cholesterol efflux.

Cranberry anthocyanin as an herbal medicine lowers plasma cholesterol by increasing excretion of fecal sterols

BackgroundInterest in using herbal medicines to treat the hypercholesterolemia is increasing. Cranberry extract could decrease plasma cholesterol, however, the active ingredients and the underlying mechanisms remain largely unknown. HypothesisThe present study was to test the hypothesis that cranberry anthocyanins (CrA) were at least one of the active ingredients responsible for the cholesterol-lowering activity of cranberry fruits via a mechanism of increasing fecal sterol excretion. MethodsForty-four hamsters were randomly divided into five groups and fed one of the five diets, namely a non-cholesterol control diet (NCD), a high-cholesterol control diet (HCD), a HCD diet supplemented with a low dose of 1% CrA (CL), a HCD diet supplemented with a high dose of 2% CrA (CH), and a HCD diet supplemented with 0.5% cholestyramine as a positive control drug (P-CTL), respectively, for six weeks. Plasma lipoprotein cholesterol was quantified using the enzymatic kits, while the gene expressions of transporters, enzymes and receptors involved in cholesterol absorption and metabolism were quantified using the quantitative RT-PCR. Fecal sterols were quantified using gas chromatography (GC). ResultsPlasma total cholesterol and aorta atherosclerotic plaque decreased dose-dependently with the increasing amounts of CrA added into diets. This was accompanied by a dose-dependent increase in excretion of both neutral and acidic sterols. CrA had no effect on the mRNA levels of intestinal Niemann-Pick C1 like 1 protein (NPC1L1), acyl CoA:cholesterol acyltransferase2 (ACAT2), microsomal triacylglycerol transport protein (MTP), and ATP binding cassette transporter 5 (ABCG5) as well as hepatic cholesterol-7α-hydroxylase (CYP7A1), 3-Hydroxy-3-methylglutaryl reductase (HMG-CoA-R), sterol regulatory element binding protein 2 (SREBP2), LDL receptor (LDL-R), and Liver X receptor alpha (LXRα). ConclusionCrA as an herbal medicine could favorably modify the lipoprotein profile in hamsters fed a high cholesterol diet by enhancing excretion of fecal neutral and acidic sterols, most likely not mediated by interaction with genes of transporters, enzymes and proteins involved in cholesterol absorption and metabolism.

Effects of Melatonin on Glucose Homeostasis, Antioxidant Ability, and Adipokine Secretion in ICR Mice with NA/STZ-Induced Hyperglycemia.

Diabetes is often associated with decreased melatonin level. The aim was to investigate the effects of different dosage of melatonin on glucose hemostasis, antioxidant ability and adipokines secretion in diabetic institute for cancer research (ICR) mice. Forty animals were randomly divided into five groups including control (C), diabetic (D), low-dosage (L), medium-dosage (M), and high-dosage (H) groups. Groups L, M, and H, respectively, received oral melatonin at 10, 20, and 50 mg/kg of BW (body weight) daily after inducing hyperglycemia by nicotinamide (NA)/ streptozotocin (STZ). After the six-week intervention, results showed that melatonin administration increased insulin level and performed lower area under the curve (AUC) in H group (p < 0.05). Melatonin could lower hepatic Malondialdehyde (MDA) level in all melatonin-treated groups and increase superoxide dismutase activity in H group (p < 0.05). Melatonin-treated groups revealed significant higher adiponectin in L group, and lower leptin/adiponectin ratio and leptin in M and H groups (p < 0.05). Melatonin could lower cholesterol and triglyceride in liver and decrease plasma cholesterol and low-density lipoprotein-cholesterol (LDL-C) in L group, and increase plasma high-density lipoprotein-cholesterol (HDL-C) in H group (p < 0.05). Above all, melatonin could decrease oxidative stress, increase the adiponectin level and improve dyslipidemia, especially in H group. These data support melatonin possibly being a helpful aid for treating hyperglycemia-related symptoms.

The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway

Controlling cholesterol levels is a major challenge in human health, since hypercholesterolemia can lead to serious cardiovascular disease. Drugs that target carbohydrate metabolism can also modify lipid metabolism and hence cholesterol plasma levels. In this sense, dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, augments usage of the glycolysis-produced pyruvate in the mitochondria increasing oxidative phosphorylation (OXPHOS). In several animal models, DCA decreases plasma cholesterol and triglycerides. Thus, DCA was used in the 70 s to treat diabetes mellitus, hyperlipoproteinemia and hypercholesterolemia with satisfactory results. However, the mechanism of action remained unknown and we describe it here. DCA increases LDLR mRNA and protein levels as well as LDL intake in several cell lines, primary human hepatocytes and two different mouse models. This effect is mediated by transcriptional activation as evidenced by H3 acetylation on lysine 27 on the LDLR promoter. DCA induces expression of the MAPK ERK5 that turns on the transcription factor MEF2. Inhibition of this ERK5/MEF2 pathway by genetic or pharmacological means decreases LDLR expression and LDL intake. In summary, our results indicate that DCA, by inducing OXPHOS, promotes ERK5/MEF2 activation leading to LDLR expression. The ERK5/MEF2 pathway offers an interesting pharmacological target for drug development.

Effect of feed supplementation with Satureja khuzistanica essential oil on performance and physiological parameters of broilers fed on wheat- or maize-based diets

ABSTRACT1. The aim of this study was to evaluate various levels of Satureja khuzistanica essential oil (SKEO) on performance and physiological parameters of broilers fed on wheat- or maize-based diets.2. Treatments consisted of two cereals (maize- or wheat-based diets) and three levels of SKEO)0, 250 and 500 mg/kg).3. Feed intake (FI) and body weight gain (BWG) decreased in broilers fed on the wheat-based diets compared to the control diet. Dietary supplementation of 500 mg/kg SKEO increased FI and BWG. Dietary SKEO supplementation was effective in improving FI and BWG only in wheat-based diets and was effective in improving feed conversion ratio (FCR) in both diets.4. Dietary supplementation of 500 mg/kg SKEO caused a significant decrease in plasma cholesterol and triglycerides. Also, plasma low-density lipoprotein concentration was decreased in broilers fed on 250 and 500 mg/kg of SKEO. Plasma cholesterol levels in birds fed on the wheat-based diets were lower than in those fed on maize-based diets.5. Dietary supplementation of 500 mg/kg SKEO increased caecal population of Lactobacillus and reduced total bacterial and Escherichia coli count. Caecal population of Lactobacillus decreased in broilers fed on the wheat-based diets.6. Digesta viscosity was increased in broilers fed on the wheat-based diets and decreased in broilers fed on 500 mg/kg SKEO compared to the control diet. Dietary SKEO supplementation was effective in reducing digesta viscosity values only in wheat-based diets.7. Villus height of the duodenum and jejunum decreased in broilers fed on the wheat-based diets. Dietary supplementation of 500 mg/kg SKEO increased villus height and villus height-to-crypt depth ratios and decreased crypt depth of the duodenum compared to the control diet.8. It can be concluded that dietary SKEO supplementation was effective in improving FI, BWG and FCR values in wheat-based diets.