Hyperlipidemic Animals Research Articles

Discovery of analogues of non-β oxidizable long-chain dicarboxylic fatty acids as dual inhibitors of fatty acids and cholesterol synthesis: Efficacy of lead compound in hyperlipidemic hamsters reveals novel mechanism

Background and aimsCholesterol and triglycerides are risk factors for developing cardiovascular disease. Therefore, appropriate cells and assays are required to discover and develop dual cholesterol and fatty acid inhibitors. A predictive hyperlipidemic animal model is needed to evaluate mechanism of action of lead molecule for therapeutic indications. Methods and resultsPrimary hepatocytes from rat, hamster, rabbit, and humans were compared for suitability to screen compounds by de novo lipogenesis (DNL) using14C-acetate. Hyperlipidemic hamsters were used to evaluate efficacy and mode of action.In rat hepatocytes DNL assay, both the central moiety and carbon chain length influenced the potency of lipogenesis inhibition. In hyperlipidemic hamsters, ETC-1002 decreased plasma cholesterol and triglycerides by 41% and 49% at the 30 mg/kg dose. Concomitant decreases in non-esterified fatty acids (−34%) and increases in ketone bodies (20%) were associated with induction of hepatic CPT1-α. Reductions in proatherogenic VLDL-C and LDL-C (−71% and −64%) occurred partly through down-regulation of DGAT2 and up-regulation of LPL and PDK4. Activation of PLIN1 and PDK4 dampened adipogenesis and showed inverse correlation with adipose mass. Hepatic concentrations of cholesteryl ester and TG decreased by 67% and 64%, respectively. Body weight decreased with concomitant decreases in epididymal fat. Plasma and liver concentrations of ETC-1002 agreed with the observed dose–response efficacy. ConclusionsTaken together, ETC-1002 reduced proatherogenic lipoproteins, hepatic lipids and adipose tissues in hyperlipidemic hamsters via induction of LPL, CPT1-α, PDK4, and PLIN1, and downregulation of DGAT2. These characteristics may be useful in the treatment of fatty livers that causes non-alcoholic steatohepatitis.

Male and Female Animals Respond Differently to High-Fat Diet and Regular Exercise Training in a Mouse Model of Hyperlipidemia

Inappropriate nutrition and a sedentary lifestyle can lead to obesity, one of the most common risk factors for several chronic diseases. Although regular physical exercise is an efficient approach to improve cardiometabolic health, the exact cellular processes are still not fully understood. We aimed to analyze the morphological, gene expression, and lipidomic patterns in the liver and adipose tissues in response to regular exercise. Healthy (wild type on a normal diet) and hyperlipidemic, high-fat diet-fed (HFD-fed) apolipoprotein B-100 (APOB-100)-overexpressing mice were trained by treadmill running for 7 months. The serum concentrations of triglyceride and tumor necrosis factor α (TNFα), as well as the level of lipid accumulation in the liver, were significantly higher in HFD-fed APOB-100 males compared to females. However, regular exercise almost completely abolished lipid accumulation in the liver of hyperlipidemic animals. The expression level of the thermogenesis marker, uncoupling protein-1 (Ucp1), was significantly higher in the subcutaneous white adipose tissue of healthy females, as well as in the brown adipose tissue of HFD-fed APOB-100 females, compared to males. Lipidomic analyses revealed that hyperlipidemia essentially remodeled the lipidome of brown adipose tissue, affecting both the membrane and storage lipid fractions, which was partially restored by exercise in both sexes. Our results revealed more severe metabolic disturbances in HFD-fed APOB-100 males compared to females. However, exercise efficiently reduced the body weight, serum triglyceride levels, expression of pro-inflammatory factors, and hepatic lipid accumulation in our model.

Tucumã (Astrocaryum aculeatum) prevents memory loss and oxidative imbalance in the brain of rats with hyperlipidemia.

Hyperlipidemia generates deposition of lipids, inflammation, and oxidative damage in cells and tissues, including those of the brain. Tucumã (Astrocaryum aculeatum) fruits contain bioactive compounds with antioxidant and anti-inflammatory effects. We evaluated the action of Tucumã extract on memory and brain cortex redox balance in hyperlipidemic rats. For 30days, Wistar rats received Tucumã extract (250mg/kg). Then, hyperlipidemia was induced by intraperitoneal administration of Poloxamer-407. Twenty-four hours later, the object recognition index was measured. The animals were euthanized for sample collection 36hr postinduction. Hyperlipidemic animals showed memory loss and an imbalance between reactive species and intrinsic antioxidants. We found that Tucumã prevented memory loss and protein and lipid oxidative damage and prompted a better antioxidant response in the cerebral cortex of rats with hyperlipidemia. These findings suggest a neuroprotective effect and nutraceutical potential of Tucumã. PRACTICAL APPLICATIONS: In the present work, we demonstrated that induced hyperlipidemia in rats caused memory loss and redox unbalance, both factors prevented by the administration of Tucumã (Astrocaryum aculeatum) extract. Two aims were fulfilled with these results. The first was to show that hyperlipidemia affected brain function through oxidative damage and concerned basic research. The second was to offer a therapy that prevented this harm and could be applied in the clinic. Tucumã has ethnopharmacological importance through the consumption of fruits or the administration of extracts and oils by a population that was shown to enjoy improved health and longevity. Here, we show evidence that Tucumã contributes to the maintenance of brain health by preventing memory loss and oxidative damage, a nutraceutical supplement that may aid the prevention of vascular, inflammatory, and brain diseases.

Establishment of blood lipids variation-based experimental hyperlipidemia animal model: a review

Nowaday, the prevalence of dyslipidemia has developed into a global public health problem. The screening of lipid-lowering active substances and the study of their mechanism have received extensive attention, and the establishment of hyperlipidemia model is the premise of relative studies. In the study, hyperlipidemic animal models established with different factors such as dietary composition, food/environmental pollution factors and drug stimulation are summarized and analyzed from the aspects of blood lipid changes, inducer ratio/dose, modeling mechanism and modeling cycle. It is shown that 4 – 8 weeks free feeding of high-fat diet and 4 – 6 weeks intragastric administration of fat emulsion can cause lipid accumulation in experimental animals; egg yolk or fat emulsion injection can cause a significant increase in plasma triglycide in animals within 2 hours – 2 days. The high-fat/high-glucose-induced C. elegans or zebrafish high-fat model can be used as a rapid screening model for lipid-lowering actives. Both food contaminant 1, 3-dichloro-2-propanol and environmental pollutant heavy metal lead can induce stable mixed hyperlipidemia; detergents Triton and poloxamer can induce an acute model with clear mechanism; and hormone can induce kidney deficiency type hyperlipidemia. Congenital dyslipidemia and gene knockout models are often applied to in-depth mechanistic studies. The establishment method of hyperlipidemia model has various advantages and disadvantages. It is necessary to establish a suitable/efficient high-fat model according to studies on the development of natural lipid-lowering active substances.

Clopidogrel Prophylaxis Abates Myocardial Ischemic Injury and Inhibits the Hyperlipidemia-Inflammation Loop in Hypercholestrolemic Mice

Platelet hyper adhesiveness orchestrates with inflammation and vascular muscle proliferation leading to atheroma formation and endothelial dysfunction. The current study aims to compare the prophylactic role of Aspirin and Clopidogrel therapy against isoproterenol-induced acute myocardial infarction (AMI), in mice on high-fat, cholesterol-rich diet (HFD-C). The animals received HFD-C with Aspirin or Clopidogrel for 8weeks and were subjected to AMI by isoproterenol. The blood lipids, inflammatory cytokines, myocardial enzymes, redox state, long pentraxin (PTX3), and matrix metalloproteinases (MMP-2 and MMP-9) activities were investigated. Antiplatelet therapy moderated the hyperlipidemia induced by HFD-C in the current study. Essentially, the total cholesterol and LDL-C levels were lower with Aspirin than with Clopidogrel therapy. Yet Aspirin and Clopidogrel each comparably lowered CK-MB, AST, MMP-2, MMP-9, and the lipid peroxidation product malondialdehyde (MDA) in the hyperlipidemic animals exposed to AMI. However, the decline in cTn-T, LDH and PTX3 levels was greater after Clopidogrel than Aspirin administration. Therefore, Clopidogrel provides greater protection against AMI than Aspirin in the hyperlipidemic mice. This could be explained by the suppression of the proinflammatory cytokines IL-6, TNF-α, TGF-1β and stabilization of the extracellular matrix through the inhibition of MMP-2 and MMP-9 activities. Furthermore, Clopidogrel demonstrated significant antioxidative action in the AMI animals, resulting in diminished MDA production and preserved CAT activity. Beside its therapeutic role in the thrombotic vascular events, Clopidogrel confers significant protection against ischemic myocardial injury by counteracting the platelet-mediated inflammation and oxidative stress associated with HFD-C consumption in animals.

Vitamin K Stimulates Gas6 Carboxylation and Inhibits Hyperlipidemia Associated Hepatic Inflammation via Arresting Monocyte-Hepatocyte Adhesion

Abstract Objectives Vitamin K (VK), an important antihemorrhagic vitamin has attracted scientific attention recently due to its diverse physiological activities beyond hemostasis. Present study for the first time systematically examined the hypothesis that circulating VK deficiency might be linked with hyperlipidemia-associated inflammatory pathophysiology and VK supplementation may ameliorate the hepatic inflammation via activating growth arrest specific 6 (Gas6) protein, an important member of the coagulation-unrelated vitamin K-dependent proteins. Methods Subjects with hyperlipidemia (n = 22) and age-matched healthy controls (n = 19) attending the institute clinical center were included in this study. High fat diet (HFD)-fed male albino mice model was used for in vivo studies. High palmitic acid (PA, 0.75 mM)-treated and GGCX knockdown monocytes and hepatocytes were employed for in vitro studies. All data were analyzed using Sigma Stat statistical software. Results Plasma levels of VK and Gla-Gas6 were significantly lower and intercellular adhesion molecule-1 (ICAM-1) was remarkably higher in hyperlipidemic subjects compared to control. Correlation studies showed that both circulatory Gla-Gas6 and VK levels were significantly and inversely correlated with ICAM-1. Interestingly, Gla-Gas6 was positively correlated with plasma VK, which suggests that VK supplementation may ameliorate the hyperlipidemia-induced inflammation via activating Gas6. Further studies with HFD-fed hyperlipidemic animals demonstrated that VK supplementation dose-dependently reduced the hepatic expression of pro-inflammatory cytokines while elevating the plasma level of Gla-Gas6 in HFD-fed mice. In vitro studies showed that VK supplementation prevented the high PA-induced hepatic inflammation in a dose-dependent manner. Furthermore, the knockdown study established the direct role of Gla-Gas6 in mediating the positive effect of VK on the management of PA-induced hepatic inflammation. Conclusions Combining all, the present study demonstrated the beneficial effect of VK supplementation on the management of hyperlipidemia-associated inflammatory events via activating VK-dependent Gas6 protein. Funding Sources Junior research fellowship to JB & Ramalingaswami fellowship to PM by DBT, Govt. of India.

Dietary supplement-wheat germ’s effect on the spectrum of lipoproteins and fatty acids in the blood of experimental hyperlipidemic animals

Dietary supplement-wheat germ’s effect on the spectrum of lipoproteins and fatty acids in the blood of experimental hyperlipidemic animals

ERK1/2-PPARγ pathway is involved in Chlamydia pneumonia-induced human umbilical vein endothelial cell apoptosis through increased LOX-1 expression

Chlamydia pneumonia (C.pn) is a common respiratory pathogen that is involved in human cardiovascular diseases and promotes the development of atherosclerosis in hyperlipidemic animal models. C.pn reportedly up-regulated lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells. Recently, the anti-atherosclerotic activity of peroxisome proliferator-activated receptor γ (PPARγ) has been documented. In the present study, we investigated the effect of C.pn on LOX-1 expression in human umbilical vein endothelial cells (HUVECs) and identified the involvement of the PPARγ signaling pathway therein. The results showed that C.pn increased the expression of LOX-1 in HUVECs in a dose- and time-dependent manner. C.pn-induced up-regulation of LOX-1 was mediated by ERK1/2, whereas p38 MAPK and JNK had no effect on this process. C.pn induced apoptosis, inhibited cell proliferation, and decreased the expression PPARγ in HUVECs. Additionally, LOX-1 activity and cell injury caused by C.pn through activation of ERK1/2 was completely inhibited by rosiglitazone, a PPARγ agonist. In conclusion, we inferred that activation of PPARγ in HUVECs suppressed C.pn-induced LOX-1 expression and cell damage by inhibiting ERK1/2 signaling.

Antihyperlipidemic effect of iridoid glycoside deacetylasperulosidic acid isolated from the seeds of Spermacoce hispida L. - A traditional antiobesity herb

Ethnobotanical relevanceThe interest on herbal health supplements for obesity is increasing globally. Our previous ethnobotanical survey in Tiruvallur district, Tamil Nadu, India indicated the use of Spermacoce hispida L. seeds for the treatment of obesity. Aim of the studyThis study was aimed to validate the traditional claim and to identify the antihyperlipidemic principle in the seeds of Spermacoce hispida using bioassay guided fractionation method. MethodsBioassay monitored fractionation of the aqueous extract from Spermacoce hispida seeds was carried out using triton WR 1339 induced hyperlipidemic animals. It yielded deacetylasperulosidic acid (DAA) as the active ingredient. Pharmacokinetic properties of DAA were predicted using DataWarrior and SwissADME tools. In vitro antiobesity and antihyperlipidemic effects of DAA were evaluated in 3T3L1 preadipocytes and HepG2 cells, respectively. The chronic antihyperlipidemic efficacy of DAA was evaluated in high fat diet fed rats. ResultsDAA did not show any mutagenic and tumorigenic properties. It bound with PPARα with comparable ligand efficiency as fenofibrate. The treatment with DAA significantly lowered the proliferation of matured adipocytes, but not preadipocytes. The treatment of steatotic HepG2 cells with DAA significantly decreased the LDH leakage by 43.03% (P < 0.05) at 50 μM concentration. In triton WR 1339 induced hyperlipidemic animals, the treatment with 50 mg/kg dose significantly lowered the TC, TG and LDL-c levels by 40.27, 46.00 and 63.65% respectively. In HFD fed animals, the treatment at 10 mg/kg decreased BMI and AC/TC ratio without altering SRBG. It also improved serum lipid, transaminases and phosphatases levels of HFD fed animals. The treatment lowered adipocyte hypertrophy and steatosis of hepatocytes. ConclusionThis preliminary report supported the traditional use of Spermacoce hispida for the treatment of obesity. Further detailed investigations on the long term safety, efficacy and molecular mode of action of Spermacoce hispida and DAA will throw more light on their usefulness for the management of obesity.

A novel AMPK activator improves hepatic lipid metabolism and leukocyte trafficking in experimental hepatic steatosis

A novel AMP-activated protein kinase (AMPK) activator, IMM-H007 (H007), has been reported to reduce serum lipid levels and inhibit lipid accumulation in the liver in hyperlipidemic animal models. However, how H007 ameliorates hepatic steatosis and inflammation remains unknown. In the present study, H007, at 200 mg/kg, reduced hepatic lipid levels and the levels of collagenous fiber in the liver in high-fat diet (HFD)-fed hamsters compared to those in the HFD group. Meanwhile, compared to the controls, H007 significantly inhibited sterol-regulatory element binding protein (SREBP)-1c and acetyl CoA carboxylase (ACC) expression by upregulating the AMPK activity, suppressing the saturated fatty acid accumulation and increasing polyunsaturated fatty acid synthesis in the liver. Compared to the controls, H007 treatment inhibited the expression of monocyte chemotactic protein (MCP-1) in fatty acid-treated HepG2 cells; suppressed leukocyte adherence and rolling on the liver microvasculature; and suppressed hepatic macrophage infiltration. H007 also suppressed the expression of nuclear factor-κB (NF-κB) p65 in fatty acid- and lipopolysaccharide-treated HepG2 cells compared to that in the controls by activating AMPK. These data suggested that H007 had a beneficial effect by improving the lipid composition in the liver and inhibiting inflammatory cell trafficking in the development of nonalcoholic fatty liver disease.

Hyperlipidemia and Allograft Rejection.

Advances in the development of immunosuppressive drug regimens have led to impressive survival rates in the year following organ transplantation. However rates of long-term graft dysfunction remain undesirably high. Recently it has been shown that co-morbidities in the patient population may affect graft survival. In mouse models, hyperlipidemia, a co-morbidity present in the majority of cardiac transplant patients, can significantly alter T cell responses to cardiac and skin allografts, and accelerate graft rejection. Here we review recent advances in our understanding of how alterations in lipids affect immune function and graft survival. Recent work in humans has highlighted the importance of controlling low density lipoprotein (LDL) levels in transplant recipients to reduce the development of chronic allograft vasculopathy (CAV). High serum levels of cholesterol containing particles leads to extensive immune system changes to T cell proliferation, differentiation and suppression. Changes in B cell subsets, and the ability of antigen presenting cells to stimulate T cells in hyperlipidemic animals may also contribute to increased organ allograft rejection. Cholesterol metabolism is a critical cellular pathway for proper control of immune cell homeostasis and activation. Increasing evidence in both human, and in mouse models shows that elevated levels of serum cholesterol can have profound impact on the immune system. Hyperlipidemia has been shown to increase T cell activation, alter the development of T helper subsets, increase the inflammatory capacity of antigen presenting cells (APC) and significantly accelerate graft rejection in several models.

Effect of DPP-4 inhibitor sitagliptin against ischemia-reperfusion (I/R) injury in hyperlipidemic animals

Hyperlipidemia is a major risk factor associated with increased risk of myocardial infarction. Dipeptidyl peptidase-4 (DPP-4) inhibitors such as sitagliptin are a class of oral anti-diabetic drugs with secondary pleiotropic effects on metabolic and cardiovascular parameters. This study aimed to determine the possible cardioprotective effects of sitagliptin on ischemia-reperfusion (I/R) injury in animals kept on high-fat diet. Male Wistar rats were fed with high-fat diet (HF) for 12 weeks, to induce hyperlipidemia. During the last two weeks of the feeding period, animals were orally treated with different doses of sitagliptin (Sitg: 25, 50, 100, and 150 mg/kg/day), or saline as a control. Heart tissues were then isolated and subjected to two different I/R-injury protocols for infarct size (IS) measurement and biochemical analysis. To test the role of NOS enzyme, NOS inhibitor (L-NAME) was injected intraperitoneally for IS evaluation. As an effective dose, Sitg (50 mg) exhibited a significant impact on IS. NOS activity increased significantly in the Sitg (50 mg) treated groups; however this protective effect was abolished in the presence of L-NAME. The protective effect of Sitg that was mediated by TRP channels in our previous study on normolipidemic animals was abrogated in animals fed with high-fat diet.

Біохімічні показники крові мурчаків за атеросклерозу на фоні застосування препаратів рослинного походження «Кардіофіл» та «Фітохол»

Cardiovascular disease is a major cause of morbidity and mortality in the United States and in many developing countries. Atherosclerosis is the most common cause of many cardiovascular diseases. It occurs by the deposition of lipids and cholesterol on the inner lining of the blood vessels, which leads to plaque formation and narrowing of the lumen. It is considered that oxidation of LDL plays a significant role in the progression of atherosclerosis. Certain studies have shown that antioxidants can delay the progression of atherosclerosis. Currently therapeutic and prophylactic herbal products are widely applied. These products affect the body comprehensively because it includes biologically active substances, macro and microelements, vitamins. “Cardiofil” and “Phytochol” are such therapeutic and prophylactic means. To determine the hypolipidemic, antisclerotic and overall impact of the “Cardiofil” and “Phytochol” to guinea pigs is the purpose of the work. Two groups (control and experimental) of 5 laboratory animals(guinea pigs) each one with an average body weight of 500 g and 1 year old were formed to carry out the experiment. All animals were kept and fed in the same way. The animals were quarantined before the experiment. Healthy guinea pigs, with good appetite and average locomotor activity were selected for the experiment. Atherosclerosis and hyperlipidemia in animals of the control and experimental groups were simulated by applications of 2 ml of a mixture that contains cholesterol and fats (lard oil and preheated sunflower oil in a ratio of 4: 1), at the cholesterol rate of 0.5 g / kg body weight, which was given to the guinea pigs for 7 days before the experiment began(every day, 30 minutes before feeding). The animals of the experimental group were given “Cardiofil” - 5 drops 3 times a day and “Phytochol” 1 drop with a small amount of water once a day for 30 days. Animals were monitored throughout the experiment, taking into account general clinical and physiological parameters. Blood was taken for examination of biochemical parameters. Animals were withdrawn from the experiment by decapitation under gas anesthesia on the 30th day of the experiment after a 12–14 hour starvation. Blood was taken from the tail vein into 5 ml tubes with a dispensing gel and a Vacusera coagulation activator to determine the biochemical parameters of blood in the guinea pigs. Blood tests were carried out using a “Stat Fax 1904+” semiautomatic biochemical analyzer using “SpineLab” reagent kits from Kharkiv, Ukraine. It was found that impaired lipoprotein metabolism for atherosclerosis was manifested by a more pronounced increase of the body weight of the control group, which in turn could lead to an increase in blood pressure, disturbances of the rhythm of the heart muscle, and a decrease of stamina. Thus, the body weight of animals of the control group on the 30th day of the experiment increased by 2.8% and by 1.9% of the experimental group animals. The study has revealed an increase of serum triglyceride content in the blood of control group animals by 1.3 times compared with the animals of the experimental group. The content of total cholesterol in the serum of the guinea pigs of the experimental group, which were given “Cardiofil” and “Phytochol” was lower by 1.8 times compared with the control group. Higher levels of HDL and LDL were found in serum of animals of the control group respectively 1.4 and 1.43 times compared with the animals of the experimental group. The atherogenic index is 1.2 times higher in the control group. Higher activity of AlAT, AsAT and creatine phosphokinase in serum of guinea pigs of the control group was found respectively in 1,2, 1,6 and 1,8 times compared with the experimental group animals. Increase of urea content by 1.06 times and decrease of total protein and creatinine content, respectively 1.1 and 0.9-fold in the serum of the control group guinea pigs, compared with the experimental group animals. The glucose content of the serum of the control group animals was 1.1-fold higher, compared to the experimental group guinea pigs. Thus, according to the obtained data, the beginning and development of atherosclerosis in guinea pigs may be influenced by diets containing both high fat and high cholesterol. The use of herbal preparations “Cardiophil” and “Fitochol” for atherosclerosis in guinea pigs exhibits their lipid-lowering and anti-sclerotic properties.

Fracture in drug-eluting stents increases focal intimal hyperplasia in the atherosclerosed rabbit iliac artery.

Drug-eluting stent (DES) strut fracture (SF) is associated with higher incidence of In-stent restenosis (ISR)-return of blockage in a diseased artery post stenting-than seen with bare metal stents (BMS). We hypothesize that concomitance of drug and SF leads to greater neointimal response. Controlled release of therapeutic agents, such as sirolimus and its analogs, or paclitaxel from has reduced tissue based DES failure modes compared to BMS. ISR is dramatically reduced and yet the implications of mechanical device failure is magnified. Bilateral Xience Everolimus-eluting stents (EES) were implanted in 20 New Zealand White rabbits on normal (n = 7) or high fat (HF)/high cholesterol (HC) (n = 13) diets. Implanted stents were intact or mechanically fractured. Everolimus concentration was as packaged or pre-eluted. After 21 days, stented vessels were explanted, resin embedded, MicroCT scanned, and analyzed histomorphometrically. Fractured EES were associated with significant (P < 0.05) increases in arterial stenosis and neointimal formation and lower lumen-to-artery area ratios compared to intact EES. Hyperlipidemic animals receiving pre-eluted EES revealed no significant difference between intact and fracture groups. SF increases intimal hyperplasia, post EES implant, and worse with more advanced disease. Pre-eluted groups, reflective of BMS, did not show significant differences, suggesting a synergistic effect of everolimus and mechanical injury, potentially explaining the lack of SF reports for BMS. Here, we report that ISR has a higher incidence with SF in EES, the clinical implication is that patients with SF after DES implantation merit careful follow-up.

Dipeptidyl peptidase 4 inhibitor anagliptin ameliorates hypercholesterolemia in hypercholesterolemic mice through inhibition of intestinal cholesterol transport.

Aims/IntroductionRecent data showed that dipeptidyl peptidase 4 (DPP‐4) inhibitors exert a lipid‐lowering effect in diabetes patients. However, the mechanism of action is not yet clearly understood. We investigated the effect of anagliptin on cholesterol metabolism and transport in the small intestine using non‐diabetic hyperlipidemic animals, to clarify the mechanisms underlying the cholesterol‐lowering action.Materials and MethodsMale apolipoprotein E (ApoE)‐deficient mice were orally administered anagliptin in the normal chow. Serum cholesterol levels and lipoprotein profiles were measured, and cholesterol transport was assessed by measuring the radioactivity in the tissues after oral loading of 14C‐labeled cholesterol (14C‐Chol). In additional experiments, effects of exendin‐4 in mice and of anagliptin in DPP‐4‐deficient rats were assessed. Effects on target gene expressions in the intestine were analyzed by quantitative polymerase chain reaction in normal mice.ResultsThe serum total and non‐high‐density lipoprotein cholesterol concentrations decreased after anagliptin treatment in the ApoE‐deficient mice. The cholesterol‐lowering effect was predominantly observed in the chylomicron fraction. The plasma 14C‐Chol radioactivity was significantly decreased by 26% at 2 h after cholesterol loading, and the fecal 14C‐Chol excretion was significantly increased by 38% at 72 h. The aforementioned effects on cholesterol transport were abrogated in rats lacking DPP‐4 activity, and exendin‐4 had no effect on the 14C‐Chol transport in ApoE‐deficient mice. Furthermore, significant decreases of the intestinal cholesterol transport‐related microsomal triglyceride transfer protein, acyl‐coenzyme A:cholesterol acyltransferase 2, ApoA2 and ApoC2 messenger ribonucleic acid expressions were observed in the mice treated with repeated doses of anagliptin.ConclusionsThese findings suggest that anagliptin might exert a cholesterol‐lowering action through DPP‐4‐dependent and glucagon‐like peptide 1‐independent suppression of intestinal cholesterol transport.

Health effects of sour cherries with unique polyphenolic composition in their fruits

Health effects of fruit consumption are confirmed by many studies. Such effects are attributed to the polyphenolic compounds accumulating in fruit skin and mesocarp tissues. They contribute to the regulation on transcriptional, post-transcriptional and epigenetic levels. Since people consume much less fruits than the recommended quantities, a new approach includes the promotion of super fruits that are extremely rich sources of specific health compounds. A comparative analysis of Hungarian stone fruit cultivars detected a huge variability in fruit in vitro antioxidant capacity and total polyphenolic content. Two outstanding sour cherry cultivars ('Pipacs 1' and 'Fanal') were identified to accumulate elevated levels of polyphenolic compounds in their fruits. Sour cherries with different polyphenolic compositions were tested against alimentary induced hyperlipidemia using male Wistar rat model. Consumption of cherry fruit had different consequences for different cultivars: consumption of 'Pipacs 1' and 'Fanal' fruits resulted in 30% lower total cholesterol levels in the sera of hyperlipidemic animals after only 10 days of treatment. However, the consumption of 'Újfehértói fürtös' fruit has not induced significant alterations in the same parameter. Other lipid parameters also reflected the short-term beneficial effects of 'Pipacs 1' and 'Fanal' fruits. We suggest that not only some tropical and berry fruits might be considered as super fruits but certain genotypes of stone fruits as well. These have indeed marked physiological effects. Since 'Pipacs 1' and 'Fanal' are rich sources of colourless polyphenolics (e.g., phenolic acids and isoflavonoids) and anthocyanins, respectively, the protective effects associated with their consumption can be attributed to different polyphenolic compounds. Orv Hetil. 2018; 159(18): 720-725.

Chitosan Nanoparticles of Gamma-Oryzanol: Formulation, Optimization, and In vivo Evaluation of Anti-hyperlipidemic Activity.

The elevated blood levels of cholesterol and low-density lipoproteins result in hyperlipidemia. The available expensive prophylactic treatments are kindred with severe side effects. Therefore, we fabricated the polymeric nanoparticles of gamma-oryzanol to achieving the improved efficacy of drug. The nanoparticles were prepared by ionic gelation method and optimized using 23 full factorial design taking drug/polymer ratio (X1), polymer/cross linking agent ratio (X2), and stirring speed (X3) as independent variables. The average particle size, percentage entrapment efficiency, and in vitro drug release at 2, 12, and 24h were selected as response parameters. The factorial batches were statistically analyzed and optimized. The optimized nanoparticles were characterized with respect to particle size (141nm) and zeta potential (+ 6.45mV). Results obtained with the prepared and characterized formulation showed 83% mucoadhesion towards the intestinal mucosa. The in vitro findings were complemented well by in vivo anti-hyperlipidemic activity of developed formulation carried out in Swiss albino mouse model. The in vivo studies showed improved atherogenic index, malondialdehyde, and superoxide dismutase levels in poloxamer-407-induced hyperlipidemic animals when treated with oryzanol and gamma-oryzanol nanoformulation. Based on our findings, we believe that chitosan-mediated delivery of gamma-oryzanol nanoparticles might prove better in terms of anti-hyperlipidemic therapeutics.

Consumption of High Fat Diet Induces Obesity Associated to Hepatic Steatosis in Rats

Introduction: The high intake of carbohydrates and lipids is one of factors that contribute to the onset of Metabolic Syndrome (MetS), a complex clinical situation which brings together, besides obesity, several cardiovascular and metabolic risk factors, including non-alcoholic fatty liver disease (NAFLD). Objective: To develop a hyperlipidemic dietetic animal model to obesity associated with NAFLD. Methodology: Male Rats Wistar (8 weeks old) were submitted to the standard diet (chow group, 11,8% kcal- lipids) and hypercaloric and hyperlipidemic during 8 weeks (HFD group, 58,4% kcal-lipids). After the dietary intervention, body weight, plasma and hepatic lipid profile (triglycerides, total cholesterol, VLDL and fatty acids) and adiposity index were evaluated. Moreover, histological assessment of hepatic lipid deposition and fibrosis, as well as the hepatic damage marker (alanine aminotransferase-ALT) were evaluated. Results and Discussion: Comparing to the chow group, HFD animals presented higher body weight, both in fasting and in the fed state, increased abdominal circumference, adiposity index, as well as plasma levels of total cholesterol and non-esterified fatty acids, characterizing the dietary phenotype of obesity. In addition, the HFD group had a significant decrease in brown adipose tissue, together with the lowest weight loss induced by 16h overnight fasting, suggesting a decrease in energy expenditure. In the liver, the HFD group presented a significant increase in the levels of triglycerides, cholesterol, VLDL and non-esterified fatty acids, and, qualitatively, increased lipid deposition and fibrosis. Together, these results associated with increased plasma ALT activity indicate NAFLD with hepatocyte damage. Conclusion: A high fat diet intake induces comorbidities that characterize MetS, such as obesity associated with decreased energy expenditure, as well as NAFLD.

Observation of pancreatic microcirculation in hyperlipidemic acute pancreatitis of hamster model

Objective To observe the effect of hyperlipidemia on pancreatic microcirculation in an intact hyperlipidemic acute pancreatitis animal moldel. Methods Among 30 healthy hamsters enrolled, 20 were fed normally while, the other 10 were given high fat feed for four weeks.Then 10 animals given normal feed with normal serum lipids and no ultrasonic changes in the organs including liver, biliary tract and pancreas, were randomly(random number) selected and divided into normal control group (C group) and acute pancreatitis group (AP group) averagely.Five animals given high fat feed with 3 times serum normal triglyceride level and no ultrasonic changes in the organs including liver, biliary tract and pancreas, were randomly selected as hyperlipidemic acute pancreatitis group(HLAP). The animals in C group were undergone fake surgery.While the animals in other two groups were carried out surgery based on Schmidt method and were injected 3.5% taurocholic acid sodium into pancreatic duct with a infusion pump. Acridine orange (2 mL/kg) was injected in the inferior vena cava 6 hours later, then laser confocal microscope fluorescence imaging system were utilized to dynamically observe pancreatic microcirculation in living animal models and the variables including average microvascular diameter (MVD), functional capillary density (FCD), microvessel flow velocity (MFV) and leukocyte adhesion were recorded. Pancreatic tissue were collected and cut slices for pathological grading. Result When compared with AP group and C group, pancreas microcirculation function index MVD(μm), FCD(piece/mm2), MFV(μm/s) in the HLAP group decreased, while leukocyte adhesion (piece/mm2) increased significantly[MVD: HLAP group 2.40±0.26 vs.AP group 5.54±0.43, C group 7.56±0.42 (P<0.05); FCD: HLAP group 4.20±0.84 vs.AP group 7.56±1.14, C group 11.40±1.14(P<0.05); MFV: HLAP group 58.80±9.63 vs.AP group 131.00±12.94, C group 224.40±15.63 (P<0.05); leukocyte adhesion: HLAP group 343.60±13.86 vs.AP group 114.00±8.03, C group 18.80±2.28; (P<0.05)]. The pancreatic pathology score was higher in HLAP group [HLAP group 10.00±1.59 vs.AP group 6.60±1.14, C group 1.00±0.71(P<0.05)]. Conclusion Hyperlipidemia may aggravate the impair ment of pancreatic microcirculation and promote microcirculation dysfunction. Key words: Pancreatitis; Hyperlipidemia; Hamster; Animal model; Microcirculation system of pancreas

Cassia auriculata flower extract attenuates hyperlipidemia in male Wistar rats by regulating the hepatic cholesterol metabolism

Hyperlipidemia in the male albino Wistar rats was induced by Triton WR – 1339. The treatment of the hyperlipidemic animals with the ethanol extract of Cassia auriculata flower (Et-CAF) exhibited a dose dependent reduction in serum triacylglycerol, total cholesterol, low density lipoprotein (LDL), very low density lipoprotein (VLDL) similar to the hyperlipidemic animals treated with standard drug atorvastatin. Hyperlipidemia altered the protein and mRNA expression levels of the key genes (SREBP-1c, ACC1, SREBP-2, HMGR, HMGS, CYP7A1, and ABCA1) in lipid metabolism and the treatment with Et-CAF (300mg/kg b. wt) reverted these levels similar to that observed with atorvastatin treated hyperlipidemic animals. These results revealed that Et-CAF extract served as an efficient anti-hyperlipidemic drug.