Animal Model Of Hyperlipidemia Research Articles

The pharmacokinetics of dabigatran in a rat model of hyperlipidaemia induced by poloxamer 407

Various pharmacokinetic changes have been reported in experimental hyperlipidemic (HL) animal models. To evaluate whether P-glycoprotein (P-gp) activity was affected in HL rats, we assessed the pharmacokinetics of dabigatran after oral administration of dabigatran etexilate (DABE); this is a dabigatran prodrug and a well-known P-gp substrate. HL and control rats exhibited similar area under the plasma concentration-time curve (AUC), total body clearance (CL), and steady state volume of distribution (Vss) values following intravenous administration of dabigatran (1 mg/kg). This suggested that the distribution and elimination of dabigatran were similar in control and HL rats. The hepatic and intestinal P-gp protein levels did not differ significantly between control and HL rats. The dabigatran AUC and extent of absolute oral bioavailability (F) values were similar in control and HL rats following oral administration of DABE (10 mg/kg as dabigatran). Therefore, there was no apparent change in intestinal P-gp activity in HL rats compared to control rats. This study revealed no significant change in P-gp expression or activity in the intestine or liver of HL rats, and similar pharmacokinetics of dabigatran. Hyperlipidaemia may not directly affect the oral absorption of P-gp substrate drugs.

Unveiling dynamic alterations of lipid droplet polarity during NAFLD-triggered lipophagy utilizing a far-red fluorescent probe with large stokes shift

Lipophagy as a form of autophagy, can degrade lipid droplets, thereby acting as a critical regulator of cellular lipid metabolism, helping maintain the intracellular lipid homeostasis. In this study, we developed LP-SCUN, a far-red fluorescent probe for pinpointing lipid droplets with high sensitivity to solvent polarity. This probe allows for in situ imaging of lipophagy, tracking how lipid droplets move from non-polar to polar environments within lysosomes, leading to noticeable changes in fluorescence signals. The triphenylamine and triethylene glycol monomethyl ether groups of LP-SCUN facilitated its selective binding toward lipid droplets. Significantly, lipophagy and subsequent formation of autolysosomes decreased the environmental polarity, leading to a significant decrease in red fluorescence intensity (λex = 500 nm and λem = 643 nm). As such LP-SCUN was suitable for the in situ and real-time tracking of the cellular lipophagic processes. With this research we used LP-SCUN to elucidate the mechanism of lipid metabolism in liver cells of palmitate-induced hyperlipidemia cell models and high-fat diet-induced hyperlipidemia animal models. The results indicated that non-alcoholic fatty liver disease (NAFLD) can trigger an increase in cell lipophagy levels, while the inhibition of cell lipophagy can effectively alleviate the damage caused by NAFLD to cells and liver tissue in mice.

Enhancing solubility and oral bioavailability of rosuvastatin through interpenetrating polymer network (IPN) nanogels: Fabrication, characterization, and in-vivo efficacy assessment

Rosuvastatin (RST) exhibits low aqueous solubility, presenting a challenge for its effective oral administration. The objective of this study is to improve the solubility of RST through the creation and assessment of interpenetrating polymer network (IPN) nanogels. The nanogels were produced via a free radical polymerization method, where hydrophilic polymers β-cyclodextrin (β-CD) and Poloxamer-407 (P407) were combined with the monomer 2-acrylamido-2-methylpropane sulfonic acid (AMPS). Comprehensive characterization of the nanogels included drug loading efficiency, solubility studies, zeta sizer measurements, sol-gel analysis, Fourier-transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), swelling studies, and in-vitro release analysis. Oral toxicity experiments were performed to verify the safety of the β-CD/Poloxamer-407-co-poly (AMPS) IPN nanogels when taken by mouth. The scanning electron microscopy (SEM) investigation unveiled a network structure characterised by porosity and sponginess. The thermal stability and complex synthesis of the nanogel components were validated by the FTIR, TGA, and DSC spectra. X-ray diffraction (XRD) analysis indicated a reduction in the crystallinity of RST within the nanogel matrices. The optimized nanogels formulation demonstrated a particle size of 185.71 ± 1.03 nm. Comparative studies with a reference product highlighted significant enhancements in drug solubility and release characteristics attributed to the fabricated nanogels. Toxicity assessments confirmed the non-toxic nature of the nanogels, supporting their biocompatibility. In-vivo studies using hyperlipidemic animal models validated the anti-hyperlipidemic efficacy of the developed nanogels. The nanogels' biocompatibility, high solubilization capacity, improved dissolution profile, rapid production process, and superior physicochemical properties underscore their potential as an effective oral delivery system for lipophilic drugs.

Evaluation of probiotic bifidobacteria strains from Iranian traditional dairy products for their anti-hyperlipidemic potential.

This study investigated the therapeutic potential of probiotic bifidobacteria, isolated from Iranian fermented dairy products, in a hyperlipidemic animal model. Bifidobacterium strains were extracted from traditional dairy samples and screened using physiological and phenotypic examinations, 16S rRNA analysis, and probiotic properties such as tolerance to gastrointestinal juice, antimicrobial activity, and antibiotic susceptibility. The ability of the screened bifidobacteria to reduce serum and liver lipids in vivo was tested using male Wistar rats. Six strains of bifidobacteria were isolated from traditional Iranian fermented dairy. These strains showed promising in vitro activity in lowering triglyceride and cholesterol, tolerance to simulated gastrointestinal juice, the ability to adhere to Caco-2 cells, acceptable antibiotic susceptibility, and a broad spectrum of antibacterial activity. The diet supplemented with isolated bifidobacteria significantly reduced serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), liver tissue lipid levels, and hepatic enzymes in animals when compared to a high-fat diet without strains (p < 0.01). Additionally, the potential probiotic-supplemented diet significantly increased bile acid excretion in the feces and upregulated hepatic CYP7A1 expression levels (p < 0.05), while NPC1L1, ACAT2, and MTP gene expressions in small intestinal cells were downregulated (p < 0.05). Bifidobacteria isolated from Iranian traditional dairy showed potential for use in the production of fermented foods that have hypolipemic activity in the host.

Exploration of the Potential Mechanism of Succus Bambusae Ameliorating Obesity and Hyperlipidemia in High-Fat Diet Apoe-/-Mice and Caenorhabditis Elegans by Network Pharmacology Combined with Transcriptomic Approach

Obesity and hyperlipidemia have become a global public health problem, and bamboo leaves have a positive intervention effect on them. As a common medicinal form of bamboo in clinical practice, the therapeutic effect and mechanism of Succus Bambusae on obesity and hyperlipidemia are still unclear. To this end, two animal models of hyperlipidemia, Apoe-/-mice and Caenorhabditis ele-gans (C. elegans), were used to study the therapeutic effect and potential mechanism of Succus Bambusae on hyperlipidemic by pharmacodynamics, network pharmacology and transcriptomics approachs. The results showed that Succus Bambusae could significantly reduce the lipid accumulation in nematodes, reduce the body weight and liver lipid accumulation in Apoe-/-mice, and significantly reduce the levels of TG and FBG in plasma. Both the arachidonic acid metabolism and the steroid hormone biosynthesis signaling pathways were included in the KEGG pathways enrichment results of network pharmacology and transcriptomics analysis. RT-qPCR results showed that XZL can effectively decrease the transcriptional levels of UGT1A5 and CYP1A1. In summary, XZL can effectively alleviate obesity and hyperlipidemia induced by high-fat diet, which is achieved by regulating the steroid hormone biosynthesis signaling pathways.

HYPOLIPIDEMIC ACTIVITY OF HIPTAGE BENGHLENSIS LEAF EXTRACTS ON HIGH FAT DIET INDUCED HYPERLIPIDAEMIC RATS

The present study was designed to evaluate the hypolipidemic effects of aqueous extract (HBAE) and ethanolic extract (HBEE) of Hiptage benghalensis leaves using a high-fat-diet induced hyperlipidemic animal model. Albino male wistar rats (120–150 g) were split into various groups, each of which had six individuals. Normal rats (group I) were received 0.3% carboxy methyl cellulose (CMC) with a standard laboratory diet, while hyperlipidemic rats (group II, III, IV, V, VI and VII) were fed high-fat diet for induction of hyperlipidemia. Hyperlipidaemic control group (group II) received 0.3% CMC (10 mL/kg/day), standard group (group III) received gemfibrozil (50 mg/kg/day, p.o.), HBAE groups (group IV and V) received aqueous extract of H. benghalensis (100 and 200 mg/kg/day, p.o.), and HBEE groups (group VI and VII) received an ethanolic extract of H. benghalensis (100 and 200 mg/kg/day, p.o.), concurrent with high fat diet for consecutive four weeks. The HBAE and HBEE treatments led to a significant (p &lt; 0.05) reduction in serum lipids (TC, TG, LDL and VLDL) and elevation in cardioprotective HDL, when compared to hyperlipidaemic rats (group II). Phytochemical screening revealed the presence of phytoconstituents such as alkaloids, flavonoids, saponins, tannins, phenolic compounds and steroids, which may be attributed to observed hypolipidemic effects. The present study’s findings concluded that HBEE (200 mg/kg, p.o.) had potent hypolipidemic effects.

Ultra-high performance liquid chromatography-quadrupole/time-of-flight mass spectrometry-based lipidomics reveals key lipid molecules as potential therapeutic targets of Polygonum cuspidatum against hyperlipidemia in a hamster model.

Polygonum cuspidatum is a homology of traditional medicine and functional food widely distributed around the world. Our previous study on the hyperlipidemic animal model demonstrated that Polygonum cuspidatum was effective in ameliorating hyperlipidemia, which is characterized by lipid disorders. Herein, the regulatory effect of Polygonum cuspidatum on lipid metabolism needs to be known if its hypolipidemic mechanism is desired to clarify. In this study, an ultra-high performance liquid chromatography-quadrupole/time-of-flight mass spectrometry-based lipidomic strategy was first applied to investigate the lipidomic patterns of high-fat diet-induced hyperlipidemic hamsters when treated with Polygonum cuspidatum. The results showed that Polygonum cuspidatum improved the lipidomic profile of hyperlipidemia. A total of 65 differential lipids related to the hypolipidemic effect of Polygonum cuspidatum were screened out and identified, and these differential lipids covered various categories, such as phosphatidylcholines, phosphatidylethanolamines, triacylglycerols, sphingomyelins and so on. Orally administrated Polygonum cuspidatum restored these differential lipids back to normal or nearly normal levels. This study adopted lipidomics to reveal the key lipid molecules as potential therapeutic targets of Polygonum cuspidatum against hyperlipidemia, which would provide a scientific basis for its clinical application.

Wogonoside improves high-fat diet-induced hyperlipidemia and aortic injury in ApoE -/- mice by upregulating SIRT1 expression

This study aimed to evaluate the effect of Wogonoside (Wog), a flavonoid monomer, on hyperlipidemia and explore its possible mechanisms. APOE -/- mice were used to establish the animal model of hyperlipidemia by feeding the high-fat diet (HFD). The serum level of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA), oil red O staining, and real-time PCR assay. The oxidative stress was measured by ELISA assay. Immunoblot assay and ELISA assay were used to detect the mechanism of Wogonoside on hyperlipidemia. We found that Wogonoside ameliorated lipid metabolism disorders in ApoE -/- mice induced by HFD (P&lt;0.01). Wogonoside also ameliorated HFD-induced inflammation in ApoE -/- mice (P&lt;0.01). Wogonoside ameliorated oxidative stress in HFD-induced ApoE -/- mice (P&lt;0.01). Further study showed that Wogonoside improved HFD-induced hyperlipidemia and inflammation by upregulating SIRT1 expression (P&lt;0.01). These results suggested that Wogonoside has the potential to be used as a promising approach for the intervention of hyperlipidemia.

Altered element homeostasis and transmethylation ability in short-term polyphenol rich supplementation in hyperlipidemic animal model

Abstract Non-alcoholic fatty liver disease is one of the most common chronic liver diseases with unclarified pathomechanism and without evidence-proven therapy. Dietary polyphenols, targeting oxidative stress, are at the center of investigations. Our aim was to examine the effects of a polyphenol rich extract on metal element homeostasis and transmethylation ability in non-alcoholic fatty liver model. A ten-day rat model was used (control group, hyperlipidemic group with fat-rich diet, hyperlipidemic group with fat-rich diet and polyphenol supplementation, N = 8 in each group). The hyperlipidemic diet increased the concentration of the majority of the elements with significantly higher contents of B, Co, Cu, Fe, Mg, Mn, Na, Ni, P, Se, Si, and Zn in the liver. Further elevation of Al, Pb, and Sn concentrations could be observed in polyphenol supplemented animals. The polyphenol supplement unexpectedly decreased the transmethylation ability of the liver (132.00 vs. 114.15 vs. 92.25 HCHO μg g−1) further. The results emphasize the possible role of altered metal and non-metal element concentrations and decreased transmethylation ability in the pathomechanism of fatty liver disease. Dietary supplementation with natural compounds may have undesirable effect as well, there is the necessity to improve the efficacy of polyphenol formulations because of their low oral bioavailability.

Effect of Washed Microbiota Transplantation on Patients With Dyslipidemia in South China.

Background and AimsAlthough the manual crude fecal microbiota transplantation (FMT) reduces blood lipids in animal models of hyperlipidemia, its clinical effect on blood lipid metabolism in patients with hyperlipidemia and hypolipidemia remains unclear, especially in the Chinese population. It was reported that washed microbiota transplantation (WMT) was safer, more precise, and more quality-controllable than the crude FMT by manual. This study aimed to investigate the feasibility and effectiveness of WMT on lipid metabolism in the Chinese population.MethodsClinical data of patients with various indications who received WMT for 1–3 treatment procedures were collected. Changes in blood lipids before and after WMT, namely, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), homeostasis model assessment of insulin resistance (HOMA-IR), liver fat attenuation, and liver stiffness measurement, were compared.ResultsA total of 177 patients (40 cases of hyperlipidemia, 87 cases with normal blood lipids, and 50 cases of hypolipidemia) were enrolled in the First Affiliated Hospital of Guangdong Pharmaceutical University. WMT has a significant therapeutic effect in reducing blood lipid levels (TC and TG) in the short- and medium term in patients with hyperlipidemia (p <0.05). Hyper blood lipid decreased to normal in the short-term (35.14%; p <0.001), and LDL-C changed to normal in the medium term (33.33%; p = 0.013). In the hypolipidemia group, 36.36% and 47.06% changed to normal in the short-term (p = 0.006) and medium term (p = 0.005) of therapeutic effects based on blood lipid levels. In the normal blood lipid group and the low-risk group of atherosclerotic cardiovascular disease (ASCVD), the change was not statistically significant, indicating that WMT does not increase the risk of blood lipid and ASCVD in the long-term.ConclusionsWMT treatment changes blood lipids in patients with hyperlipidemia and hypolipidemia without serious adverse events, with no risk for increasing blood lipids and ASCVD in the long-term. There were significant decreased TC, TG, and LDL-C levels in the medium term of WMT treatment for hyperlipidemia. Therefore, the regulation of gut microbiota by WMT may indicate a new clinical method for the treatment of dyslipidemia.

Berberine-loaded liposomes for oral delivery: Preparation, physicochemical characterization and in-vivo evaluation in an endogenous hyperlipidemic animal model

Berberine (BBR) is a plant-origin quaternary isoquinoline alkaloid presenting exogenous cholesterol lowering and anti-hyperlipidemia therapeutic effects. The aim of this study was to design and generate BBR-loaded proliposomes (PLs) as solid templates for high-dose liposomes and consequently, to enhance the oral bioavailability and therapeutic effect of BBR. An air-suspension coating (layering) method was used for generating BBR-loaded PLs. The size, distribution size, morphology, and entrapment efficiency (EE) of the final reconstituted liposomes were assessed. The oral bioavailability and endogenous cholesterol lowering effects of BBR loaded in liposomes were investigated in rats and mice, respectively. The BBR-loaded PLs showed a smooth BBR-embedded film around micron-scale carrier particles (mannitol). The reconstituted BBR-loaded liposomes had a nano-scale average size (116.6 ± 5.8 nm), narrow size distribution (polydispersity index, PDI 0.269 ± 0.038), and high EE (87.8 ± 1.0%). The oral bioavailability of reconstituted BBR-loaded liposomes at a dose of 100 mg/kg in rats was increased even 628% compared to that obtained with pure BBR (according to 90% confidence interval). The BBR-loaded liposomes at the daily oral dose 100 mg/kg in P-407- reduced total cholesterol, triglycerides and low-density lipoprotein cholesterol (LDL-C) in hyperlipidemic mice by 15.8%, 38.2%, and 57.0%, respectively.

Effects of Colchicine in a Rat Model of Diet-Induced Hyperlipidemia.

Inflammation and hyperlipidemia play an essential role in the pathophysiology of endothelial dysfunction as well as atherosclerotic plaque formation, progression and rupture. Colchicine has direct anti-inflammatory effects by inhibiting multiple inflammatory signaling pathways. The purpose of our study was to evaluate colchicine activity in an animal model of hyperlipidemia induced by diet. A total of 24 male rats (wild type, WT) were divided into three groups: group one fed with a basic diet (BD) (WT + BD, n = 8), group two fed with a high-fat diet (HFD) (WT + HFD, n = 8)), and group three which received HFD plus drug treatment (colchicine, 0.5 mg/kg, i.p., daily administration). Total cholesterol, LDL-, HDL-cholesterol and triglycerides were determined. In addition, plasma transaminases, inflammation of oxidative stress markers, were measured. Tissue samples were evaluated using hematoxylin-eosin and red oil stain. At the end of the study, rats presented increased serum lipid levels, high oxidative stress and pro-inflammatory markers. The aortic histopathological section revealed that HFD induced signs of endothelial dysfunction. Colchicine treatment significantly resolved and normalized these alterations. Moreover, colchicine did not influence NAFLD activity score but significantly increased ALT and AST levels, suggesting that colchicine amplified the hepatocellular injury produced by the diet. Colchicine reduces plasma lipid levels, oxidative stress and inflammation markers and leads to more favorable histopathologic vascular and cardiac results. However, the adverse effects of colchicine could represent an obstacle to its safe use.

Evaluation of Hypolipidemic and Hepatoprotective Effects of Linum usitatissimum L. Seeds on Hypercholesterolemic Rats

Background: Hyperlipidaemia is a chronic progressive disease, which encompasses various genetic and acquired conditions resulting in inappropriately elevated lipid levels in humans. Several preclinical and clinical studies have demonstrated that dietary supplementation with Linum Usitatissimum have beneficial cardiovascular effects like antihypertensive action, antiatherogenic effects, lowering of cholesterol, anti-inflammatory action and inhibition of arrhythmia. There are few studies on hepatoprotective effects of flax seeds in hyperlipidemic animal models. Aim and objectives: Hence, this study was undertaken to evaluate the hypolipidemic and hepatoprotective effect of Linum seeds.&#x0D; Methods: The study was conducted for the period of two months in Department of Pharmacology KIMS, Bhubaneswar. Total 36 Albino wistar rats were taken and divided into 6 groups containing 6 rats each. Group II was hypercholesterolemic (HC) control, Group III was treatment control and Group IV to VI rats were given different doses of extract. Blood samples were taken at the end of two months.&#x0D; Results: All the values are expressed as Mean±SD (standard deviation). Significant decrease in lipid parameters and liver enzymes is seen at the end of two months in all 3 groups receiving the extract, where the highest dose of extract used, is near to the standard drug.&#x0D; Conclusion: From this study, it can be concluded that the addition of the flaxseeds to the diet may alleviate the rise in circulating cholesterol levels induced by the high cholesterol diet through its content of alfa-linolenic acid (ALA) and lignins. The hepatoprotective role of flaxseed in hypercholesterolaemia has also been demonstrated in this this study.

Tetrahydropalmatine Alleviates Hyperlipidemia by Regulating Lipid Peroxidation, Endoplasmic Reticulum Stress, and Inflammasome Activation by Inhibiting the TLR4-NF-κB Pathway.

Hyperlipidemia (HLP) is a lipid metabolism disorder that can induce a series of cardiovascular and cerebrovascular diseases, such as atherosclerosis, myocardial infarction, coronary heart disease, and stroke, which seriously threaten human health. Tetrahydropalmatine (THP) is a component of the plant Rhizoma corydalis and has been shown to exert hepatoprotective and anti-inflammatory effects in HLP. However, whether THP regulates lipid peroxidation in hyperlipidemia, endoplasmic reticulum (ER) stress and inflammasome activation and even the underlying protective mechanism against HLP remain unclear. An animal model of HLP was established by feeding a high-fat diet to golden hamsters. Our results showed that THP reduced the body weight and adipose index; decreased the serum content of ALT, AST, TC, TG, and LDL-C; decreased the free fatty acid hepatic lipid content (liver index, TC, TG, and free fatty acid); inhibited oxidative stress and lipid peroxidation; extenuated hepatic steatosis; and inhibited ER stress and inflammasome activation in high-fat diet-fed golden hamsters. In addition, for the first time, the potential mechanism by which THP protects against HLP through the TLR4-NF-κB signaling pathway was demonstrated. In conclusion, these data indicate that THP attenuates HLP through a variety of effects, including antioxidative stress, anti-ER stress, and anti-inflammatory effects. In addition, THP also inhibited the TLR4-NF-κB signaling pathway in golden hamsters.

KLF4 Upregulation in Atherosclerotic Thoracic Aortas: Exploring the Protective Effect of Colchicine-based Regimens in a Hyperlipidemic Rabbit Model

Inflammatory dysregulation of KLF4 is related to atheromatosis. In the present study, we explored the impact of colchicine-based regimens on the development of thoracic aortic atheromatosis and KLF4 expression. Twenty-eight New Zealand White rabbits were divided to 4 groups. The control group (n=6) was fed standard chow, group A (n=6) was fed chow enriched with 1% w/w cholesterol, group B (n=8) was fed the same cholesterol-enriched diet plus 2 mg/kg body weight/day colchicine and 250 mg/kg body weight/day fenofibrate, while group C (n=8) was also fed the same diet plus 2 mg/kg body weight/day colchicine and 15 mg/kg body weight/day N-acetylcysteine. After 7 weeks, all animals were euthanized, and their thoracic aortas were isolated. Atherosclerotic plaque area was estimated with morphometric analysis. KLF4 expression was quantified with quantitative RT-PCR. Group A developed significantly more atherosclerosis compared to group B (MD: 13.67, 95% CI: 7.49-19.84) and C (MD: 20.29, 95% CI: 14.12-26.47). Colchicine with N-acetylcysteine resulted in more pronounced reduction in the extent of atherosclerotic plaques compared to colchicine/fibrate (MD: 6.62, 95% CI: 0.90-12.34). Group A exhibited significantly greater KLF4 expression compared to group B (MD: 4.94, 95% CI: 1.11-8.77) and C (MD: 9.94, 95% CI: 6.11-13.77). Combining colchicine with N-acetylcysteine instead of fenofibrate (MD: 5.00, 95% CI: 1.45-8.54) led to a more robust reduction in KLF4 expression. In the present hyperlipidemic animal model, colchicine-based regimens curtailed de novo atherogenesis and KLF4 overexpression in thoracic aortas.

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.

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.

Pyrogallol-Phloroglucinol-6,6-Bieckolon Attenuates Vascular Smooth Muscle Cell Proliferation and Phenotype Switching in Hyperlipidemia through Modulation of Chemokine Receptor 5.

Hyperlipidemia induces vascular smooth muscle cell (VSMC) proliferation and phenotype switching from contractile to synthetic. This process is involved in arterial remodeling via the chemokine ligand 5 (CCL5)/chemokine receptor 5 (CCR5) pathway. Arterial remodeling is related to atherosclerosis or intimal hyperplasia. The purpose of this study was to evaluate whether pyrogallol-phloroglucinol-6,6-bieckol (PPB) from E. cava reduces VSMC proliferation and phenotype switching via the CCL5/CCR5 pathway. The CCL5/CCR5 expression, VSMC proliferation and phenotypic alterations were evaluated using a cell model of VSMC exposed in hyperlipidemia, and an animal model of mice fed a high-fat-diet (HFD). The expression of CCL5/CCR5 increased in both the cell and animal models of hyperlipidemia. Treatment with PPB decreased CCL5/CCR5 expression in both models. The expression of contractile markers of VSMCs, including alpha-smooth muscle actin (α-SMA), smooth muscle myosin heavy chain (SM-MHC), and smooth muscle protein 22 alpha (SM22α), were decreased by hyperlipidemia and restored after treatment with PPB. The silencing of CCR5 attenuated the effects of PPB treatment. VSMC proliferation and the intima-media thickness of the aortas, increased with HFD and decreased after treatment with PPB. The VSMC proliferation ratio and messenger ribonucleic acid (mRNA) expression of cell cycle regulatory factors increased in the in vitro model and were restored after treatment with PPB. PPB treatment reduced VSMC proliferation and phenotype switching induced by hyperlipidemia through inhibition of the CCL5/CCR5 pathway.

Lipid-lowering effect and mechanism of Danhong Injection on hyperlipidemia rats based on lipid metabolism disorder

The animal model of hyperlipidemia in rats was established to investigate the lipid-lowering effect and mechanism of Danhong Injection on hyperlipidemic rats. SD rats were selected as the research object. The rats in normal group were fed with basic diet, and the rats in other groups were fed with high-fat diet to establish hyperlipidemia model. The successfully modeled rats were randomly divided into model group, Danhong Injection low, medium, high dose(1.0, 2.0, 4.0 mL·kg~(-1)) groups, and simvastatin(2.0 mg·kg~(-1)) group. Danhong Injection groups received intraperitoneal administration, and simvastatin group received intragastrical administration, once a day for 4 weeks. At the first, second, third, and fourth weekends after administration, blood was collected from the orbital vein to detect the levels of total cholesterol(TC), triglyceride(TG), low-density lipoprotein cholesterol(LDL-C), and high-density lipoprotein cholesterol(HDL-C), and then the atherosclerosis index(AI) was calculated. After 4 weeks of administration, the animals were sacrificed, and their heart, liver, spleen, lung, kidney and adipose tissue were extracted and weighed respectively to calculate the organ index of each group. The expressions of acyl-coaoxidase 1(Acox1), adenosine 5'-monophosphate(AMP)-activated protein kinase alpha(AMPK-α), bile salt export pump(BSEP), peroxisome proliferator-activated receptor gamma(PPAR-γ), catalase(CAT) and superoxide dismutase(SOD) mRNA in liver tissues were detected by fluorescence quantitative PCR; the content of cholesteryl ester transfer protein(CETP) and lecithin cholesterol acyltransferase(LCAT) in serum was detected by ELISA. The results showed that as compared with the normal group, the levels of serum TC, TG and LDL-C in the model group were significantly increased, and the level of HDL-C was significantly decreased, indicating that the hyperlipidemia rat model was successfully constructed. As compared with the model group, Danhong Injection could decrease the contents of TC, TG, LDL-C and increase the content of HDL-C in hyperlipidemia rats; reduce the body weight of hyperlipidemia rats, and reduce the liver weight, liver index, fat weight and fat index; it had no significant effect on the main organ indexes such as heart, spleen, lung and kidney; but it could increase the expressions of Acox1, AMPK-α, BSEP, PPAR-γ, CAT and SOD mRNA in liver tissues of rats; it could also reduce the level of CETP and increase the level of LCAT in serum; and the regulatory effect of Danhong Injection groups all showed a dose-dependent effect. It can be concluded that Danhong Injection can regulate the blood lipid contents, reduce the blood lipid levels and alleviate the accumulation of body fat in rats with hyperlipidemia. The mechanism may be related to inhibiting lipid metabolism disorder and oxidative stress induced by high-fat diet feeding, and improving the imbalance of lipid transport system.

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.