Hepatic HMG-CoA Reductase Activity Research Articles

Ocimum gratissimum enhances insulin sensitivity in male Wistar rats with dexamethasone-induced insulin resistance.

The antidiabetic activities of Ocimum gratissimum (OG) leaf extract are well documented in experimental diabetes induced by beta cell destruction resulting in hypoinsulinemia. There is however paucity of data on its effect in conditions characterized by hyperinsulinemia. This study therefore investigated the effect of OG on insulin resistance induced by dexamethasone in male Wistar rats. Twenty male Wistar rats grouped as control, normal + OG, Dex and Dex + OG were used. Control and normal + OG received normal saline while Dex and Dex + OG received dexamethasone (1mg/kg, i.p) followed by distilled water or OG (400mg/kg) for 10days. Levels of fasting blood glucose (FBG), insulin, HOMA-IR, liver and muscle glycogen, hexokinase activities, hepatic HMG CoA reductase activity were obtained. Histopathology of pancreas and liver tissues was carried out using standard procedures. Body weight reduced significantly in the Dex and Dex + OG groups compared with the control. FBG (147.8 ± 9.93mg/dL), insulin (2.98 ± 0.49 µIU/ml) and HOMA-IR (1.11 ± 0.22) of Dex animals were higher than the control (FBG = 89.22 ± 6.53mg/dL; insulin = 1.70 ± 0.49 µIU/ml; HOMA-IR = 0.37 ± 0.04). These were significantly reduced in the Dex + OG (FBG = 115.31 ± 5.93mg/dL; insulin = 1.85 ± 0.11µIU/ml; HOMA-IR = 0.53 ± 0.08) compared with Dex. Glycogen content and hexokinase activities were increased in the Dex + OG. Increased pancreatic islet size, hepatic steatosis and HMG Co A reductase activity were observed in the Dex but reduced in Dex + OG. OG promotes cellular glucose utilization and reduces hepatic fat accumulation in Wistar rats with insulin resistance induced by dexamethasone. Further study to identify the involved signal transduction will throw more light on the observed effects.

Ezetimibe attenuates experimental diabetes and renal pathologies via targeting the advanced glycation, oxidative stress and AGE-RAGE signalling in rats

The current in-vivo study was premeditated to uncover the protective role of ezetimibe (EZ) against advanced glycation endproducts (AGEs)-related pathologies in experimental diabetes. Our results showed that EZ markedly improved the altered biochemical markers of diabetes mellitus (DM) (FBG, HbA1c, insulin, microalbumin, and creatinine) and cardiovascular disease (in-vivo lipid/lipoprotein level and hepatic HMG-CoA reductase activity) along with diminished plasma carboxymethyl-lysine (CML) and renal fluorescent AGEs level. Gene expression study revealed that EZ significantly down-regulated the renal AGEs-receptor (RAGE), nuclear factor-κB (NFκB-2), transforming growth factor-β (TGF-β1), and matrix metalloproteinase-2 (MMP-2) mRNA expression, however, the neuropilin-1 (NRP-1) mRNA expression was up-regulated. In addition, EZ also maintained the redox status via decreasing the lipid peroxidation and protein-bound carbonyl content (CC) and increasing the activity of high-density lipoprotein (HDL)-associated-paraoxonase-1 (PON-1) and renal antioxidant enzymes as well as also protected renal histopathological features. We conclude that EZ exhibits antidiabetic and reno-protective properties in diabetic rats.

Amelioration of neuropilin-1 and RAGE/matrix metalloproteinase-2 pathway-induced renal injury in diabetic rats by rosuvastatin

Advanced glycation end-products (AGEs) induce the production of reactive oxygen species (ROS) and extra cellular matrix (ECM) degradation via suppression of neuropilin-1 (NRP-1) and interaction with AGE-receptors (RAGE). This study aimed to reveal whether modulation of NRP-1 by rosuvastatin (RT) prevents AGE-induced renal injury via targeting RAGE/matrix metalloproteinase-2 (MMP-2) signaling in diabetic rats. Treatment with RT ameliorated the altered level of markers of glycemic control, renal injury, cholesterol, triglyceride (TG) and hepatic HMG-CoA reductase activity; the level of circulatory carboxymethyl-lysine (CML) and the accumulation of fluorogenic-AGEs in renal tissue was reduced; the expression of renal NRP-1, a checkpoint target, was stimulated; the transcription of RAGE, NF?B-2, TGF-?1 and MMP-2 was suppressed; the circulatory carbonyl content (CC) and paraoxonase-1 (PON-1) activity was ameliorated, and renal histopathological features were attenuated as evidenced by improved glomerular appearance, Bowman?s space and abundant podocytes in kidneys. In conclusion, RT exhibited the potential to counteract diabetes and AGE-induced renal pathologies via stimulation of NRP-1, suppression of RAGE, and of genes responsible for ECM disintegration (MMP-2) and the inflammatory response (NF?B-2).

Hypolipidemic Activity of Pleurotus florida against Triton WR 1339 Induced Hyperlipidemia

Pleurotus florida (Oyster mushroom) belongs to the family Pleurotaceae and widely consumed all over the world. The aqueous ethanolic extract of the fruiting body of P.florida was evaluated for hypolipidemic activity. Hyperlipidemia was induced with the help of Triton WR 1339 (100mg/Kg b.w.) administered via intraperitoneal injection. Atorvastatin (2.5 mg/Kg b.w) was used as the standard drug. Different concentrations of aqueous ethanolic extract of P. florida (500, 250, and 100 mg/Kg b.w) were given orally before triton administration. The serum lipid profile was assayed and showed significant hypolipidemic activity compared to the control group (Triton alone). The activity of HMG CoA reductase was assayed using hydroxylamine hydrochloride. Hepatic HMG CoA reductase activity was significantly decreased in the treated group as compared to the control. The inhibition of lipid peroxidation was also assayed. A significant reduction in lipid peroxidation was seen in groups treated with extract compared to control. Lovastatin was also isolated from fruiting bodies and culture filtrate and screened using Thin Layer Chromatography. Lovastatin (sigma) was used as the standard. The finding suggests the significant hypolipidemic activity of the aqueous ethanolic extract of P. florida.

Hypolipidemic activity of Pleurotus florida against Triton WR 1339 induced Hyperlipidemia

Pleurotus florida (Oyster mushroom) belongs to the family Pleurotaceae and is one of the widely used edible mushrooms. The aqueous ethanolic extract of the fruiting body of P.florida was evaluated for hypolipidemic activity. Hyperlipidemia was induced with the help of Triton WR 1339 (100mg/Kg b.w.) administered via intraperitoneal injection. Atorvastatin (2.5 mg/Kg b.w) was used as the standard drug. Different concentrations of aqueous ethanolic extract of P.florida (500, 250, and 100mg/Kg b.w) were given orally before triton administration. The serum lipid profile was assayed and showed significant hypolipidemic activity compared to the control group (Triton alone). The activity of HMG CoA reductase was assayed using hydroxylamine hydrochloride. Hepatic HMG CoA reductase activity was significantly decreased in the treated group as compared to control. The inhibition of lipid peroxidation was also assayed. A significant reduction in lipid peroxidation was seen in groups treated with extract compared to control. Lovastatin was also isolated from fruiting bodies and culture filtrate and screened using Thin Layer Chromatography. Lovastatin (sigma) was used as the standard. The finding suggests the significant hypolipidemic activity of the aqueous ethanolic extract of P.florida.

Dietary caffeic acid, ferulic acid and coumaric acid supplements on cholesterol metabolism and antioxidant activity in rats

This study was designed to test the lipid-lowering and antioxidative activities of three phenolic compounds, caffeic acid, ferulic acid and coumaric acid. Four groups of rats were given a semisynthetic diet containing 3% of cholesterol for 6 weeks. The control group only received a high cholesterol diet, whereas the other three groups received a diet including 0.2% of caffeic acid, 0.2% of ferulic acid and 0.2% of coumaric acid. The caffeic acid, ferulic acid and coumaric acid significantly lowered the plasma lipid and hepatic cholesterol levels compared to those in the control (p < 0.05). The hepatic HMG-CoA reductase activity was significantly lower in the caffeic acid group than in the ferulic acid and coumaric acid groups (p < 0.05), while the hepatic ACAT activity was significantly lower in the caffeic acid, ferulic acid and coumaric acid groups compared to the control group (p < 0.05). The overall potential of the antioxidant system was significantly enhanced by the caffeic acid, ferulic acid and coumaric acid supplements as the plasma and hepatic TBARS levels were lowered while the hepatic SOD activities and GSH concentration were elevated in the high-cholesterol-fed rats (p < 0.05). Furthermore, these results indicated that the supplementation of caffeic acid, ferulic acid and coumaric acid boosted the antioxidant activity in rats and promoted the excretion of neutral sterol and acidic sterol (p < 0.05), thereby leading to a decreased absorption of dietary cholesterol as well as lower plasma, hepatic cholesterol and promoted excretion of fecal sterols.

Hyperglycemia exacerbates dyslipidemia-induced changes in uptake, synthesis, and transporters of bile acids in rats: Assessment of restorative potentials of ALA and EPA + DHA

In this study, under dyslipidemia (D) and dyslipidemia with diabetes (DD) conditions, we assessed the intestinal bile acid (BA) uptake, BA transporter expression and de novo BA synthesis in rats. The restorative potentials n-3 fatty acids [{α-linolenic acid (ALA), DD+canola oil (CNO)} and eicosapentaenoic acid (EPA)+docosahexaenoic acid (DHA), DD+fish oil (FO)}] were also assessed. DD group had significantly (p < 0.05) increased intestinal BA uptake and Asbt and Osta/b mRNA expression, increased serum BA level, decreased hepatic Ntcp, Bsep and Cyp7a1 mRNA expression, increased hepatic HMG-CoA reductase activity, increased hepatic Fxr and Shp mRNA expression, decreased hepatic Lrh-1 and Hnf4a mRNA expression and decreased fecal BA level, when compared to control, D, DD+CNO, and DD+FO group. Our data show for the first time that, hyperglycemia exacerbates dyslipidemia-induced dysregulation of BA metabolism and transport. Dietary EPA+DHA exhibited superior effect than ALA in normalizing dyslipidemia and hyperglycemia-induced disturbances.

Investigating The Role of Novel Bioactive Compound from Ficus Virens Ait on Cigarette Smoke Induced Oxidative Stress and Hyperlipidemia in Rats.

The present study is premeditated to extenuate the role of Ficus virens extract and its bioactive compound on cigarette smoke, an important risk factor for CVD, induced oxidative stress and hyperlipidemia. Cigarette smoke (CS) exposure to rats results in significant loss of body weight and increases blood carbon monoxide saturation (carboxyhemoglobin), nicotine, plasma TC, TG, and LDL-C levels but reduced level of antiatherogenic HDL-C. Moreover, owing to substantial oxidative stress generated in rats due to cigarette smoke a significant increase in plasma and erythrocytes lipid peroxidation products were observed which was well correlated with increase in ex-vivo BDC (48%) and MDA (53%) level (p < 0.001). Simultaneous administration of FVBM extract at higher dose (100 mg/rat) and F18 (n-Octadecanyl-O-α-D-glucopyranosyl(6'→1'')-O-α-D-glucopyranoside) compound to CS-exposed rats effectively blocked the increase in plasma lipid and lipoprotein levels (p < 0.001) which was due to the marked suppression in the hepatic HMG-CoA reductase activity (p < 0.001) and significantly inhibit the lipid peroxidation process thus preventing the membrane damage, LDL oxidation, and in turn subsequent atherosclerosis. Thus, the results clearly demonstrated the protective role of FVBM extract and F18 compound in risk factor induced cardiovascular disease.

Treatment with the natural FXR agonist chenodeoxycholic acid reduces clearance of plasma LDL whilst decreasing circulating PCSK9, lipoprotein(a) and apolipoprotein C-III.

The natural farnesoid X receptor (FXR) agonist chenodeoxycholic acid (CDCA) suppresses hepatic cholesterol and bile acid synthesis and reduces biliary cholesterol secretion and triglyceride production. Animal studies have shown that bile acids downregulate hepatic LDL receptors (LDLRs); however, information on LDL metabolism in humans is limited. Kinetics of autologous 125 I-LDL were determined in 12 male subjects at baseline and during treatment with CDCA (15 mg kg-1 day-1 ). In seven patients with gallstones treated with CDCA for 3 weeks before cholecystectomy, liver biopsies were collected and analysed for enzyme activities and for specific LDLR binding. Serum samples obtained before treatment and at surgery were analysed for markers of lipid metabolism, lipoproteins and the LDLR modulator proprotein convertase subtilisin/kexin type 9 (PCSK9). Chenodeoxycholic acid treatment increased plasma LDL cholesterol by ~10% as a result of reduced clearance of plasma LDL-apolipoprotein (apo)B; LDL production was somewhat reduced. The reduction in LDL clearance occurred within 1 day after initiation of treatment. In CDCA-treated patients with gallstones, hepatic microsomal cholesterol 7α-hydroxylase and HMG-CoA reductase activities were reduced by 83% and 54%, respectively, and specific LDLR binding was reduced by 20%. During treatment, serum levels of fibroblast growth factor 19 and total and LDL cholesterol increased, whereas levels of 7α-hydroxy-4-cholesten-3-one, lathosterol, PCSK9, apoA-I, apoC-III, lipoprotein(a), triglycerides and insulin were reduced. Chenodeoxycholic acid has a broad influence on lipid metabolism, including reducing plasma clearance of LDL. The reduction in circulating PCSK9 may dampen its effect on hepatic LDLRs and plasma LDL cholesterol. Further studies of the effects of other FXR agonists on cholesterol metabolism in humans seem warranted, considering the renewed interest for such therapy in liver disease and diabetes.

Quercetin regulates hepatic cholesterol metabolism by promoting cholesterol-to-bile acid conversion and cholesterol efflux in rats

Quercetin, a common member of the flavonoid family, is widely present in plant kingdom. Despite that quercetin is implicated in regulating cholesterol metabolism, the molecular mechanism is poorly understood. We hypothesized that quercetin regulates cholesterol homeostasis through regulating the key enzymes involved in hepatic cholesterol metabolism. To test this hypothesis, we compared the profile of key enzymes and transcription factors involved in the hepatic cholesterol metabolism in rats with or without quercetin supplementation. Twenty male Wistar rats were randomly divided into control and quercetin-supplemented groups. Serum total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total bile acids in feces and bile were measured. Hepatic enzymatic activities were determined by activity assay kit and high-performance liquid chromatography–based analyses. The messenger RNA (mRNA) and protein expressions were determined by reverse transcriptase polymerase chain reaction and Western blot analyses, respectively. The results showed that the activity of hepatic cholesterol 7α-hydroxylase, a critical enzyme in the conversion of cholesterol to bile acids, was significantly elevated by quercetin. The expression of cholesterol 7α-hydroxylase, as well as liver X receptor α, an important transcription factor, was also increased at both mRNA and protein levels by quercetin. However, quercetin exposure had no impact on the activity of hepatic HMG-CoA reductase, a rate-limiting enzyme in the biosynthesis of cholesterol. We also found that quercetin treatment significantly increased ATP binding cassette transporter G1 mRNA and protein expression in the liver, suggesting that quercetin may increase hepatic cholesterol efflux. Collectively, the results presented here indicate that quercetin regulates hepatic cholesterol metabolism mainly through the pathways that promote cholesterol-to-bile acid conversion and cholesterol efflux.

Bioactivity guided fractionation and hypolipidemic property of a novel HMG-CoA reductase inhibitor from Ficus virens Ait.

BackgroundThe current perspective for the search of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor has been shifted towards a natural agent also having antioxidant property. Thus, this study was intended to isolate and identify the bioactive compounds from methanolic extract of Ficus virens bark (FVBM) and to evaluate their antioxidant, HMG-CoA reductase inhibitory and hypolipidemic activity.MethodsBioactivity guided fractionation and isolation of bioactive compound from FVBM extract has been done to isolate and characterize the potent HMG-CoA reductase (HMGR) inhibitor with antioxidant activity by using repeated extensive column chromatography followed by spectroscopic methods, including Infrared (IR), 1H & 13C nuclear magnetic resonance (NMR) and Mass spectrum analysis. The in vitro HMGR inhibition and enzyme kinetic assay was determined using HMG-CoA as substrate. In addition, antioxidant activity of the new isolated compound, was measured using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and FRAP value. In-silico molecular informatics of HMGR enzyme type inhibition and pharmacokinetics data of the new compound was further evaluated through molecular docking and ADME-T studies. Further, in-vivo hypolipidemic property of FVBM extract and newly isolated compound was also analyzed in triton-WR 1339 induced rats.ResultsThereby, we report the discovery of n-Octadecanyl-O-α-D-glucopyranosyl(6′ → 1″)-O-α-D-glucopyranoside (F18) as a novel HMG-CoA reductase inhibitor with strong antioxidant property. This inhibitor exhibited not only higher free radical scavenging activity but also marked HMG-CoA reductase inhibitory activity with an IC50 value of 84 ± 2.8 ng/ml. This inhibitory activity concurred with kinetic study that showed inhibition constant (Ki) of 84 ng/ml via an uncompetitive mode of inhibition. The inhibition was also corroborated by molecular docking analysis and in silico pharmacokinetics data. The in vivo study revealed that administration of FVBM extract (at higher dose, 100 mg/rat) and the inhibitor (1 mg/rat) to Triton WR-1339-induced hyperlipidemic rats significantly ameliorated the altered levels of plasma lipids and lipoproteins including hepatic HMG-CoA reductase activity; this effect was comparable to the effect of standard drug atorvastatin.ConclusionsThe in vitro, in silico and in vivo results clearly demonstrated the antioxidant potential and therapeutic efficacy of the inhibitor as an alternate drug against hyperlipidemia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-015-0013-6) contains supplementary material, which is available to authorized users.

Amoxillin- and pefloxacin-induced cholesterogenesis and phospholipidosis in rat tissues.

BackgroundTo investigate whether amoxillin and pefloxacin perturb lipid metabolism.MethodsRats were treated with therapeutic doses of each antibiotic for 5 and 10 days respectively. Twenty four hours after the last antibiotic treatment and 5 days after antibiotic withdrawal, blood and other tissues (liver, kidney, brain, heart and spleen) were removed from the animals after an overnight fast and analysed for their lipid contents.ResultsBoth antibiotics produced various degrees of compartment-specific dyslipidemia in the animals. While plasma and erythrocyte dyslipidemia was characterised by up-regulation of the concentrations of the major lipids (cholesterol, triglycerides, phospholipids and free fatty acids), hepatic and renal dyslipidemia was characterised by cholesterogenesis and phospholipidosis. Splenic dyslipidemia was characterised by cholesterogenesis and decreased phospholipid levels. Cardiac and brain cholesterol contents were not affected by the antibiotics. A transient phospholipidosis was observed in the brain whereas cardiac phospholipids decreased significantly. Lipoprotein abnormalities were reflected as down-regulation of HDL cholesterol. Furthermore, the two antibiotics increased the activity of hepatic HMG-CoA reductase. Although erythrocyte phospholipidosis was resolved 5 days after withdrawing the antibiotics, dyslipidemia observed in other compartments was still not reversible.ConclusionOur findings suggest that induction of cholesterogenesis and phospholipidosis might represent additional adverse effects of amoxillin and pefloxacin.

Attenuation of Streptozotocin-Induced Lipid Profile Anomalies in the Heart, Brain, and mRNA Expression of HMG-CoA Reductase by Diosgenin in Rats.

Diabetes mellitus is associated with significant morbidity and mortality that contributes to pathogenesis of cardiovascular diseases. Diosgenin, a naturally occurring aglycone, is present abundantly in fenugreek. The steroidal saponin is being used as a traditional medicine for diabetes. The present study has investigated the effects of diosgenin on lipid profile in the heart and brain, mRNA expression, and hepatic HMG-CoA reductase (HMGR) activity of streptozotocin-induced diabetic rats. In our study, diosgenin was administered (40mg/kg b.w.) orally for 45days to control animals and experimentally induced diabetic rats. The effects of diosgenin on glucose, plasma insulin, cholesterol, triglycerides, free fatty acids, and phospholipids (PLs) in the heart and brain were studied. The levels of glucose, cholesterol, triglycerides, free fatty acids, PLs, and HMGR activity were increased significantly (P<0.05) whereas plasma insulin level was decreased in diabetic rats. Administration of diosgenin to diabetic rats significantly reduced blood glucose, cholesterol, triglycerides, free fatty acids, PLs levels, and also HMGR activity. In addition, the plasma insulin level was increased in diosgenin-treated diabetic rats. The above findings were correlated with histological observations of the heart and brain. The results showed that administration of diosgenin remarkably increased plasma insulin level with absolute reduction of blood glucose, lipid profile, and HMGR level when compared to diabetic control rats. The results have suggested that diosgenin prevents hypercholesterolemia and hepatosteatosis by modulation of enzymatic expression that is associated with cholesterol metabolism.

Mitigating role of thymoquinone rich fractions from Nigella sativa oil and its constituents, thymoquinone and limonene on lipidemic-oxidative injury in rats.

Therapeutic role of Nigella sativa (NS) seed oil fractions, methanolic extract (ME) and volatile oil (VO) and their constituents, thymoquinone (TQ) and limonene (LMN) in relation to lipidemic-oxidative stress in Wistar rats was determined. The total phenolic contents of NS seed oil and their ME and VO extracts were 320.00 ± 3.00, 300.12 ± 0.04 and 288.41 ± 0.01 mg gallic acid equivalents per 100 g of NS oil, respectively. Their Fe+2 chelating activities were 870.00 ± 2.00, 222.31 ± 5.80 and 38.59 ± 1.43 mg EDTA equivalents per 100 g of NS oil, respectively. These fractions and compounds exhibited strong antioxidant activities against 2,2-diphenyl-1-picryl hydrazyl, 2,2-azinobis-3-ethylbenzothiazoline-6-sulfonic acid, nitric oxide and hydroxyl radicals. Potential antiperoxidative effects of these fractions and compounds were also observed in liposome, and lipidemic-induced lipid peroxidation in atherogenic suspension fed rats, pretreated with 100 mg ME, 20 mg VO, 10 mg pure TQ or 200 mg LMN for 30 days. ME containing ω-6 linoleic acid and palmitic acid natural compounds was highly effective against lipidemic oxidative stress than VO extract possessing thymol and isothymol phenolic natural antioxidant compounds. TQ, principal compound shared to both the extracts. The test fractions and compounds effectively reduced the erythrocyte and liver lipid peroxidation markers, conjugated diene, lipid hydroperoxide and malondialdehyde to near normal levels in the order ME > TQ > VO > LMN, by directly counteracting free radicals as well as suppressing hepatic HMG-CoA reductase activity. Our findings demonstrated that these natural products, preferably ME possess significant antioxidant activities, and may be recommended as new potential sources of natural antioxidants.

Ameliorative effect of Pracparatum mungo extract on high cholesterol diets in hamsters

This study was designed to test the lipid-lowering and antioxidative activities of Pracparatum mungo extract (PME), in comparison to its components berberine and glycyrrhizin in cholesterol-fed hamsters. The PME and berberine significantly lowered the atherogenic index compared to glycyrrhizin and the control (P < 0.05). The hepatic HMG-CoA reductase activity was significantly lower in the PME and berberine groups than in the glycyrrhizin group (P < 0.05), while the hepatic ACAT activity was significantly decreased by all treatments with respect to the high cholesterol fed group (P < 0.05). The overall potential of the antioxidant system was significantly enhanced by the PME, berberine and glycyrrhizin supplements as the plasma and hepatic TBARS levels were lowered while the hepatic superoxide dismutase activity and glutathione levels, HMG-CoA reductase, LDL receptor, PPAR, SREBP-2 and CYP7A1 mRNA expressions were increased by the treatments of PME and berberine in comparison with the high cholesterol fed hamsters (P < 0.05). Collectively, these results suggest that the supplementation of PME, berberine and glycyrrhizin increased antioxidant activity in hamsters. Furthermore, we observed that PME and berberine groups promoted the excretion of neutral and acidic sterols (P < 0.05), that could contribute to explain the lower plasma and hepatic cholesterol levels found in the treated animals.

Dietary Coenzyme Q10 Suppressed Hepatic Hydroxymethylglutaryl-CoA Reductase Activity in Laying Hens

The effects of dietary coenzyme Q10 (CoQ10) on cholesterol metabolism in laying hens were investigated. Dietary CoQ10 significantly reduced egg yolk cholesterol content and suppressed hepatic hydroxymethylglutaryl-CoA reductase (HMGR) activity. It is therefore likely that CoQ10 acts as an HMGR inhibitor in the livers of laying hens, which in turn results in a reduction in egg-yolk cholesterol.

Elucidation of mechanisms of actions of thymoquinone-enriched methanolic and volatile oil extracts from Nigella sativa against cardiovascular risk parameters in experimental hyperlipidemia.

BackgroundNigella sativa belonging to the Ranunculaceae family has been reported to use for thousands of years as protective and curative traditional medicine against a number of diseases. GC-MS analysis of methanolic extract (ME) and volatile oil (VO) extracted from Nigella sativa seed oil was performed by two different mass spectrometry libraries, WIlEY8 and NIST05s. The cholesterol lowering and antioxidant actions of VO and ME fractions were investigated in atherogenic suspension fed rats.MethodsIn this study, four groups of male Wistar rats were used: normolipidemic control (NLP-C), hyperlipidemic control (HLP-C), methanolic extract (HLP-ME) and volatile oil treated (HLP-VO) groups for 30 days of duration. P value < 0.05 was assumed as significant data in groups.ResultsAdministration of atherogenic suspension to male Wistar rats for 30 days resulted in a marked increase of plasma triglycerides and total cholesterol, and significant change in plasma lipoprotein levels along with a decrease in antioxidant arylesterase activity in hyperlipidemic control (HLP-C) group. The oral feeding of 100 mg ME or 20 mg VO per rat/day effectively reduced the plasma triglycerides to near normal level, while high density lipoprotein cholesterol and its subfraction along with arylesterase activity levels were significantly increased. The test fractions elicited a significant decrease in hepatic HMG-CoA reductase activity. The fractions significantly blocked the ex vivo basal and in vitro maximal formation of conjugated diene and malondialdehyde, and lengthened the lag times of low density lipoprotein, small dense low density lipoprotein and large buoyant low density lipoprotein. ME possessing ω-6 linoleic acid along with palmitic acid active compounds was more effective than VO extract containing thymol and isothymol phenolic antioxidant compounds, thymoquinone phenolic compound common to the both extracts, via reduction in hepatic HMG-CoA reductase activity as well as antioxidant mechanisms.ConclusionThe both extracts especially, ME significantly improve cardiovascular risk parameters in treated rats, and can be used in reactive oxygen species disorders such as cardiovascular diseases.

Su1684 Adenosine Regulates Cholangiocyte IL-6 Secretion via the A2B Receptor

Background. Although the kidney is believed to play a minor role in bile acid (BA) excretion, chronic renal failure (CRF) has been reported to be associated with increased serum bile acid levels and alterations in BA homeostasis. According to a recent report, rats studied 3 weeks after 5/6 nephrectomy and fed a high-protein diet exhibited increased activities of hepatic HMG-CoA reductase (HMG-CoAR) and cholesterol 7 alpha-hydroxylase (Cyp7a1), despite normal corresponding mRNA levels. Design and Methods. This study was designed to examine the effects of naturally progressing CRF of longer duration on the hepatic and renal mRNA and protein levels of the bile acid synthesizing enzyme Cyp7a1 and the bile acid transporters, Ntcp, Bsep, Mrp3, Ost-alpha and OST-beta. Sprague-Dawley rats were randomized to the CRF group (5/6 nephrectomy) or to the sham-operated, placebo-treated normal control group. They were allowed free access to regular rat chow and were analyzed 8 weeks after surgery. Results obtained in CRF rats were compared to those obtained in rats that had undergone uninephrectomy (UNX). Results. The CRF group exhibited significantly increased plasma cholesterol and bile acid concentrations. Hepatic Cyp7a1 mRNA, and protein levels were almost identical in the two groups. Hepatic Mrp3, Ostα and Ost-β expression was increased at both the mRNA and protein levels, suggesting increased basolateral efflux of bile acids into basolateral blood. However, no such changes in bile acid transporter expression were observed in kidney. In UNX rats, similar changes in plasma bile acid levels and in the expression of bile acid transporters were found. We hypothesize, that the increase in plasma bile acids is an early event in the progression of CRF and is caused by increased efflux across the basolateral hepatocyte membrane.

Su1681 Hypoxia Induces Dysregulation of Lipid Metabolism in HEPG2 Cells via Activation of HIF-2a

Background. Although the kidney is believed to play a minor role in bile acid (BA) excretion, chronic renal failure (CRF) has been reported to be associated with increased serum bile acid levels and alterations in BA homeostasis. According to a recent report, rats studied 3 weeks after 5/6 nephrectomy and fed a high-protein diet exhibited increased activities of hepatic HMG-CoA reductase (HMG-CoAR) and cholesterol 7 alpha-hydroxylase (Cyp7a1), despite normal corresponding mRNA levels. Design and Methods. This study was designed to examine the effects of naturally progressing CRF of longer duration on the hepatic and renal mRNA and protein levels of the bile acid synthesizing enzyme Cyp7a1 and the bile acid transporters, Ntcp, Bsep, Mrp3, Ost-alpha and OST-beta. Sprague-Dawley rats were randomized to the CRF group (5/6 nephrectomy) or to the sham-operated, placebo-treated normal control group. They were allowed free access to regular rat chow and were analyzed 8 weeks after surgery. Results obtained in CRF rats were compared to those obtained in rats that had undergone uninephrectomy (UNX). Results. The CRF group exhibited significantly increased plasma cholesterol and bile acid concentrations. Hepatic Cyp7a1 mRNA, and protein levels were almost identical in the two groups. Hepatic Mrp3, Ostα and Ost-β expression was increased at both the mRNA and protein levels, suggesting increased basolateral efflux of bile acids into basolateral blood. However, no such changes in bile acid transporter expression were observed in kidney. In UNX rats, similar changes in plasma bile acid levels and in the expression of bile acid transporters were found. We hypothesize, that the increase in plasma bile acids is an early event in the progression of CRF and is caused by increased efflux across the basolateral hepatocyte membrane.

Effect of RYR, MFA and MFB on serum lipids and antioxidant activity in rats

summary Background & aims: This study was designed to test the lipid-lowering and antioxidative activities of red yeast rice (RYR), in comparison to its components monasfluore A (MFA) and monasfluore B (MFB) in cholesterol-fed rats. Methods: The control group only received cholesterol supplemented diet, whereas the other three groups received the same diet added with 1% RYR, or 1% MFA, or 1% MFB. Results: All treatments (RYR, MFA and MFB) reduced the atherogenic index. Simply, MFA and MFB are statistically but slightly more effective than RYR (55e58% reduction versus 46% reduction). The MFA and MFB significantly lowered the atherogenic index compared to the RYR and control (P < 0.05). The hepatic HMG-CoA reductase activity was significantly lower in the MFA group than in the RYR and MFB groups (P < 0.05), while the hepatic ACAT activity was significantly decreased by all treatments with respect to the high cholesterol fed group (P < 0.05). The overall potential of the antioxidant system was significantly enhanced by the RYR, MFA and MFB supplements as the plasma and hepatic TBARS levels were lowered while the hepatic superoxide dismutase activity and glutathione levels were increased by the treatments in comparison with the high cholesterol fed rats (P < 0.05). Conclusions: Collectively, these results suggest that the supplementation of RYR, MFA and MFB increased antioxidant activity in rats. Furthermore, we observed that all treatments promoted the excretion of neutral and acidic sterols (P < 0.05), that could contribute to explain lower plasma and, hepatic cholesterol levels found in treated animal.