Protective Effects of Ethanolic Extract of Zingiber officinale Rhizome on the Development of Metabolic Syndrome in High‐Fat Diet‐Fed Rats

Abstract: Metabolic syndrome, including obesity, dyslipidaemia, hyperglycaemia and insulin resistance that predisposes type 2 diabetes is a major disease problem around the world and a plethora of herbal medicines are claimed to be effective in controlling these disorders. The rhizome of Zingiber officinale (Zingiberaceae) is commonly used as a spice in various foods and beverages. Apart from its other traditional medical uses, Z. officinale has been used to control diabetes and dyslipidaemia. In the present study, the protective effects of an ethanolic extract of Z. officinale on the development of metabolic syndrome were investigated in a high‐fat diet‐fed rat model at doses of 100, 200 and 400 mg/kg body weight. The marked rise in body weights, glucose, insulin, total cholesterol, LDL cholesterol, triglycerides, free fatty acids and phospholipids in serum of the rats that followed 6 weeks of high‐fat diet treatment were significantly reduced by Z. officinale treatment. However, no significant change in serum HDL cholesterol was observed either with high‐fat diet or Z. officinale compared to both control groups. The present results provide scientific evidence to substantiate the traditional use of Z. officinale in preventing metabolic disorders.     

Eugenosedin‐A prevents hyperglycaemia,hyperlipidaemia and lipid peroxidation in C57BL/6J mice fed a high‐fat diet

Objectives Eugenosedin‐A is a serotonin (5‐hydroxytryptamine; 5‐HT) 5‐HT_{1b /2a} and _α1/α2/β1‐adrenoceptor blocker with anti‐oxidative, anti‐inflammatory and free‐radical scavenging activities. Previous reports demonstrated that 5‐HT_2a blockers could diminish hyperlipidaemia. This study therefore aimed to investigate the possible uses and mechanisms of eugenosedin‐A and other agents in treating hyperlipidaemia. Methods C57BL/6J mice were randomly divided into seven groups, fed a regular diet or a high‐fat diet alone or supplemented with one of five agents: eugenosedin‐A, ketanserin, prazosin, propranolol or atorvastatin (5 mg/kg p.o.) for 8 weeks. Key findings Compared with the regular diet, the mice fed the high‐fat diet had significantly higher body weight and glucose, insulin and lipid levels. Brain malondialdehyde concentration was increased and liver glutathione peroxidase activity decreased. Addition of eugenosedin‐A to the high‐fat diet resulted in less weight gain and reduced hyperglycaemia, hyperinsulinaemia and hyperlipidaemia. Lipid and glucose homeostasis were related to decreased hepatic lipogenesis mRNAs and proteins (sterol regulatory element binding protein 1a, fatty acid synthase, sterol‐CoA desaturase) and restored adipose peroxisome proliferator‐activated receptor γ expression. Eugenosedin‐A also enhanced low‐density lipoprotein receptor mRNA expression. Conclusions Eugenosedin‐A may improve plasma lipid metabolism by increasing low‐density lipoprotein receptor and peroxisome proliferator‐activated receptor γ expression and diminishing sterol regulatory element binding protein 1a, fatty acid synthase and sterol‐CoA desaturase. Reduction of plasma glucose and lipid levels may, in turn, reduce insulin concentration, which would explain the marked improvement in obesity‐related hyperglycaemia and hyperlipidaemia. Furthermore, eugenosedin‐A affected malondialdehyde concentration and glutathione peroxidase activity, suggesting it may have anti‐peroxidation effects in mice fed a high‐fat diet.     

Attenuation of liver pro-inflammatory responses by Zingiber officinale via inhibition of NF-kappa B activation in high-fat diet-fed rats

Abstract: The aim of this study was to investigate whether treatment with a ginger (Zingiber officinale) extract of high‐fat diet (HFD)‐fed rats suppresses Nuclear factor‐kappa B (NF‐κB)‐driven hepatic inflammation and to subsequently explore the molecular mechanisms in vitro. Adult male Sprague‐Dawley rats were treated with an ethanolic extract of Zingiber officinale (400 mg/kg) along with a HFD for 6 weeks. Hepatic cytokine mRNA levels, cytokine protein levels and NF‐κB activation were measured by real‐time PCR, Western blot and an NF‐κB nuclear translocation assay, respectively. In vitro, cell culture studies were carried out in human hepatocyte (HuH‐7) cells by treatment with Zingiber officinale (100 μg/mL) for 24 hr prior to interleukin‐1β (IL‐1β, 8 ng/mL)‐induced inflammation. We showed that Zingiber officinale treatment decreased cytokine gene TNFα and IL‐6 expression in HFD‐fed rats, which was associated with suppression of NF‐κB activation. In vitro, Zingiber officinale treatment decreased NF‐κB‐target inflammatory gene expression of IL‐6, IL‐8 and serum amyloid A1 (SAA1), while it suppressed NF‐κB activity, IκBα degradation and IκB kinase (IKK) activity. In conclusion, Zingiber officinale suppressed markers of hepatic inflammation in HFD‐fed rats, as demonstrated by decreased hepatic cytokine gene expression and decreased NF‐κB activation. The study demonstrates that the anti‐inflammatory effect of Zingiber officinale occurs at least in part through the NF‐κB signalling pathway.     

Taurine prevents high‐fat diet‐induced‐hepatic steatosis in rats by direct inhibition of hepatic sterol regulatory element‐binding proteins and activation of AMPK

This study investigated if the protective effect of taurine against high fat diet‐induced hepatic steatosis involves modulating the hepatic activity of 5' AMP‐activated protein kinase (AMPK) and levels/activity of the sterol regulatory element‐binding proteins‐1/2 (SREBP1/2). Rats were divided into four groups (n = 12/group) as (a) STD, fed standard diet (3.85 kcal/g); (b) STD + taurine (500 mg/kg); (c) HFD, fed HFD (4.73 kcal/g); and (d) HFD + taurine. All treatments were conducted for 12 weeks. Independent of food intake or modulating glucose or insulin levels, taurine administration to STD and HFD‐fed rats significantly lowered weekly weight gain and the accumulation of the retroperitoneal, visceral and subcutaneous fats. In both groups, taurine also reduced serum and hepatic levels of triglycerides and cholesterol and reduced hepatic mRNA and protein levels of fatty acid synthase (FAS), acetyl CoA carboxylase‐1 (ACC‐1), HMG‐CoA‐reductase and HMG‐CoA synthetase. In control rats only, taurine reduced hepatic levels of mature forms of sterol regulatory element‐binding proteins (SREBP)‐1/2. In HFD‐fed rats, taurine reduced SREBP‐1/2 precursor and mature forms in the livers of HFD‐fed rats. Besides, taurine significantly increased levels of glutathione (GSH), the activity of superoxide dismutase (SOD), and the activity of AMPK and its downstream β‐oxidation genes including peroxisome proliferator‐activated receptor‐α (PPAR‐α) and carnitine palmitoyltransferase (CPT‐1) in the livers of both the control and HFD‐fed rats. In conclusion, taurine protects against HFD‐induced hepatic steatosis stimulating antioxidant levels, and concomitant stimulating hepatic β‐oxidation and suppressing lipid synthesis, mediated by activation of AMPK and suppression of SREBP‐1.     

Curcumin Attenuates Diet‐Induced Hepatic Steatosis by Activating AMP‐Activated Protein Kinase

Curcumin is a well‐known component of traditional turmeric (Curcuma longa), which has been reported to prevent obesity and diabetes. However, the effect of curcumin on hepatic lipid metabolism remains unclear. The aim of this study was to examine the effects of curcumin on hepatic steatosis in high‐fat/cholesterol diet (HFD)‐induced obese mice. Male C57BL/6J mice were fed a normal diet (ND), HFD or HFD with 0.15% curcumin (HFD+C) for 11 weeks. We found that curcumin significantly lowered the body‐weight and adipose tissue weight of mice in the HFD+C group compared with the findings for the HFD group (p < 0.05). The levels of total cholesterol, fasting glucose and insulin in serum were decreased, and HFD‐induced impairment of insulin sensitivity was improved by curcumin supplementation (p < 0.05). Curcumin protected against the development of hepatic steatosis by reducing hepatic fat accumulation. Moreover, curcumin activated AMP‐activated protein kinase (AMPK) and elevated the gene expression of peroxisome proliferator‐activated receptor alpha. By contrast, curcumin suppressed the HFD‐mediated increases in sterol regulatory element‐binding protein‐1, acetyl‐CoA carboxylase 1, fatty acid synthase and cluster of differentiation 36 expression. Taken together, these findings indicate that curcumin attenuates HFD‐induced hepatic steatosis by regulating hepatic lipid metabolism via AMPK activation, suggesting its use as a therapeutic for hepatic steatosis.     

Hypolipidaemic activity of orally administered diphenyl diselenide in Triton WR‐1339‐induced hyperlipidaemia in mice

Objectives A significant association between the trace element selenium and hyper‐cholesterolaemia has been reported. This study was designed to investigate a potential hypolipidaemic effect of diphenyl diselenide ((PhSe)₂) in Triton WR‐1339‐induced hyperlipidaemia in mice. Methods Triton was administered intraperitoneally (400 mg/kg) to overnight‐fasted mice to develop acute hyperlipidaemia. (PhSe)₂ was administered orally (10 mg/kg) 30 min before Triton. At 24 h after Triton injection, blood samples were collected to measure plasma lipid levels. The hepatic thiobarbituric acid reactive substances and ascorbic acid levels as well as catalase and glutathione peroxidase activity were recorded. Key findings (PhSe)₂ administration significantly lowered total cholesterol, non‐high‐density lipoprotein‐cholesterol and triglycerides, whilst it increased high‐density lipoprotein‐cholesterol levels in plasma of hyperlipidaemic mice. Neither oxidative stress nor the antioxidant effect of (PhSe)₂ was observed in the mouse liver in this experimental protocol. Conclusions These findings indicated that (PhSe)₂ was able to lower plasma lipid concentrations. Further studies are needed to elucidate the exact mechanism by which (PhSe)₂ exerted its hypolipidaemic effect in the management of hyperlipidaemia and atherosclerosis.     

Comparative evaluation of the hypolipidemic effects of coconut water and lovastatin in rats fed fat–cholesterol enriched diet

The coconut water presents a series of nutritional and therapeutic properties, being a natural, acid and sterile solution, which contains several biologically active components, l-arginine, ascorbic acid, minerals such as calcium, magnesium and potassium, which have beneficial effects on lipid levels. Recent studies in our laboratory showed that both tender and mature coconut water feeding significantly (P < 0.05) reduced hyperlipidemia in cholesterol fed rats [Sandhya, V.G., Rajamohan, T., 2006. Beneficial effects of coconut water feeding on lipid metabolism in cholesterol fed rats. J. Med. Food 9, 400–407]. The current study evaluated the hypolipidemic effect of coconut water (4 ml/100 g body weight) with a lipid lowering drug, lovastatin (0.1/100 g diet) in rats fed fat–cholesterol enriched diet ad libitum for 45 days. Coconut water or lovastatin supplementation lowered the levels of serum total cholesterol, VLDL + LDL cholesterol, triglycerides and increased HDL cholesterol in experimental rats (P < 0.05). Coconut water feeding decreased activities of hepatic lipogenic enzymes and increased HMG CoA reductase and lipoprotein lipase activity (P < 0.05). Incorporation of radioactive acetate into free and ester cholesterol in the liver were higher in coconut water treated rats. Coconut water supplementation increased hepatic bile acid and fecal bile acids and neutral sterols (P < 0.05). Coconut water has lipid lowering effect similar to the drug lovastatin in rats fed fat–cholesterol enriched diet.     

Mechanism of action of hypolipemic drugs]

Hypolipemic drugs decrease the plasmatic concentrations of atherogenic lipoproteins, especially LDL. Two main drug families are used: fibrates and inhibitors of HMG CoA reductase. Fibrates act essentially as an activator of lipoprotein lipase and by increasing the catabolism of triglyceride rich lipoproteins. Further, they have a slight and non specific inhibitory effect on HMG CoA reductase activity, while, the new drug family of "statines" have a high, specific inhibitory effect on this essential enzyme of the cholesterol synthesis pathway. This enzymatic inhibition decreases the cholesterol synthesis and increases the activity of the hepatic LDL receptors, which are in charge of LDL elimination from the body. Resins entrap biliary salts and increase the cholesterol loss in feces and induce an over expression of the LDL receptors of the hepatocytes. Probucol inhibits atherogenesis by decreasing both LDL and HDL cholesterol and delaying LDL oxidative processing which is now believed to be one of the major factors of atherogenicity.     

Hypolipidemic activity of Phellinus rimosus against triton WR-1339 and high cholesterol diet induced hyperlipidemic rats

Patients with the risk for atherosclerotic disease will be targeted to reduce the existing hyperlipidemia. The hypolipidemic activity of Phellinus rimosus was studied using triton WR-1339 and high cholesterol diet (HCD) induced models. The triton induced elevated lipid profile was attenuated by P. rimosus or standard drug atorvastatin. Similarly, administration of P. rimosus along with HCD significantly decline serum triglyceride, total cholesterol, low-density lipoprotein, with elevating the high-density lipoprotein. Thiobarbituric acid reacting substances in heart and liver significantly decreased; where as activity of enzymatic antioxidants and level of reduced glutathione were significantly increased. In both models, P. rimosus extract showed a significant ameliorative effect on the elevated atherogenic index as well as LDL/HDL-C ratio. The hypolipidemic activity of P. rimosus can be ascribed to its inhibitory effect on the liver HMG CoA reductase activity. The results suggest the possible therapeutic potential of this fungus as hypolipidemic agent.     

Effect of ketanserin tartrate on HMG CoA reductase and LDL receptor activity in cultured human skin fibroblasts

In man ketanserin tartrate reduces plasma LDL cholesterol. To clarify the mechanism of this effect the effect of ketanserin on 3-hydroxy-3-methylglutaryl (HMG) CoA reductase and LDL receptor activity in cultured human skin fibroblasts has been examined. After incubation with ketanserin for 14 h HMG CoA reductase activity was decreased in a dose-dependent manner up to 300 ng/ml (550 nM) without changing the free cholesterol content in the cells. Ketanserin increased specific binding and specific internalization of 125I-LDL dose-dependently. There was a significant inverse relationship between the percentage changes in HMG CoA reductase and LDL receptor activity. It appears that ketanserin induces up-regulation of LDL receptor activity by direct suppression of HMG CoA reductase, and this may be one mechanism by which plasma LDL-cholesterol is reduced by ketanserin.     

Ferulic acid improves lipid and glucose homeostasis in high‐fat diet‐induced obese mice

Ferulic acid (FA) is a plant phenolic acid that has several pharmacological effects including antihyperglycaemic activity. Thus, the objective of this study is to investigate the effect of FA on glucose and lipid metabolism in high‐fat diet (HFD)‐induced obese mice. Institute for Cancer Research (ICR) mice were fed a HFD (45 kcal% fat) for 16 weeks. At the ninth week of induction, the obese mice were orally administered with daily FA doses of 25 and 50 mg/kg for the next eight weeks. The results show that FA significantly reduced the elevated blood glucose and serum leptin levels, lowered the insulin resistance, and increased the serum adiponectin level. Moreover, serum lipid level, and liver cholesterol and triglyceride accumulations were also reduced. The histological examination showed clear evidence of a decrease in the lipid droplets in liver tissues and smaller size of fat cells in the adipose tissue in the obese mice treated with FA. Interestingly, FA reduced the expression of hepatic lipogenic genes such as sterol regulatory element‐binding protein 1c (SREBP1c), fatty acid synthase (FAS), and acetyl‐CoA carboxylase (ACC). It could also up‐regulate hepatic carnitine palmitoyltransferase 1a (CPT1a) gene and peroxisome proliferator‐activated receptor alpha (PPARα) proteins. The FA treatment was also found to suppress the protein expressions of hepatic gluconeogenic enzymes, phosphoenolpyruvate carboxylase (PEPCK) and glucose‐6‐phosphatase (G6Pase). In conclusion, the findings of this study demonstrate that FA improves the glucose and lipid homeostasis in HFD‐induced obese mice probably via modulating the expression of lipogenic and gluconeogenic genes in liver tissues.     

Modulatory effect of Inula racemosa Hook. f. (Asteraceae) on experimental atherosclerosis in guinea‐pigs

Objectives Inula racemosa Hook. f. is indicated for precordial chest pain in Ayurveda. In this study, the effects of a hexane (IrH) and an alcohol extract (IrA) of Inula racemosa on atherosclerosis induced by a high‐fat diet in guinea‐pigs were investigated. Methods After 30 days on a high‐fat diet (guinea‐pig pellet diet + 0.2% w/w cholesterol) six animals were killed and evaluated for the onset of early atherosclerotic changes in coronary artery, aorta and major organs. The remaining animals were assigned to 5 groups of six animals each and fed for the following 90 days with a pellet diet + 0.15% w/w cholesterol (positive control) along with 100 mg/kg IrA, 100 mg/kg IrH or 10 mg/kg atorvastatin calcium. The normal control group received only the pellet diet. At the end of experimental period, serum lipid levels, heart and liver antioxidant status, area of lipophilic aortic lesions and histopathology of coronary artery were estimated. Key findings IrA decreased total cholesterol, triglycerides, low‐density lipoprotein cholesterol and the atherogenic index, and increased high‐density lipoprotein cholesterol compared with the positive control. It scavenged thiobarbituric acid reactive substances and increased reduced glutathione in liver, and enhanced superoxide dismutase and glutathione peroxidase in heart. Aortic lesion area and % bodyweight increase was least in the IrA‐treated group. Coronary artery changes due to the high‐fat diet were reversed by the extracts. The observed effects are presumably mediated by phenolics in IrA and sesquiterpene lactones in IrH. Conclusions The results demonstrate the anti‐atherogenic effect of I. racemosa, thus validating the cardioprotective and anti‐obesity claims in traditional medicine.     

Taurine ameliorates cholesterol metabolism by stimulating bile acid production in high‐cholesterol‐fed rats

This study was designed to investigate the effects of dietary taurine on cholesterol metabolism in high‐cholesterol‐fed rats. Male Sprague‐Dawley rats were randomly divided into two dietary groups (n = 6 in each group): a high‐cholesterol diet containing 0.5% cholesterol and 0.15% sodium cholate, and a high‐cholesterol diet with 5% (w/w) taurine. The experimental diets were given for 2 weeks. Taurine supplementation reduced the serum and hepatic cholesterol levels by 37% and 32%, respectively. Faecal excretion of bile acids was significantly increased in taurine‐treated rats, compared with untreated rats. Biliary bile acid concentrations were also increased by taurine. Taurine supplementation increased taurine‐conjugated bile acids by 61% and decreased glycine‐conjugated bile acids by 53%, resulting in a significant decrease in the glycine/taurine (G/T) ratio. Among the taurine‐conjugated bile acids, cholic acid and deoxycholic acid were significantly increased. In the liver, taurine supplementation increased the mRNA expression and enzymatic activity of hepatic cholesterol 7α‐hydroxylase (CYP7A1), the rate‐limiting enzyme for bile acid synthesis, by three‐ and two‐fold, respectively. Taurine also decreased the enzymatic activity of acyl‐CoA:cholesterol acyltransferase (ACAT) and microsomal triglyceride transfer protein (MTP). These observations suggest that taurine supplementation increases the synthesis and excretion of taurine‐conjugated bile acids and stimulates the catabolism of cholesterol to bile acid by elevating the expression and activity of CYP7A1. This may reduce cholesterol esterification and lipoprotein assembly for very low density lipoprotein (VLDL) secretion, leading to reductions in the serum and hepatic cholesterol levels.     

Novel action of 7‐O‐galloyl‐d‐sedoheptulose isolated from Corni Fructus as a hypertriglyceridaemic agent

Objectives We investigated the lipid‐lowering activity of 7‐O‐galloyl‐d ‐sedoheptulose, an active component of Corni Fructus, and related mechanisms. Methods Rats were fed a high‐fructose diet for 6 days, followed by treatment with 7‐O‐galloyl‐d ‐sedoheptulose, 5, 10 or 20 mg/kg per day, or fenofibrate (positive control). Key findings The high‐fructose diet induced an increase in body weight, hypertriglyceridaemia, hyperglycaemia and hypertension. Administration of 7‐O‐galloyl‐d ‐sedoheptulose significantly reduced the levels of triglyceride in the serum and liver (being more effective than fenofibrate) but did not lead to changes in liver weight or hepatic function, whereas fenofibrate increased the liver weight markedly. The preventive effect of 7‐O‐galloyl‐d ‐sedoheptulose against the accumulation of triglyceride and cholesterol was related to the up‐regulation of peroxisome proliferator‐activated receptor α expression. Conclusions The present study supports the role of 7‐O‐galloyl‐d ‐sedoheptulose as a promising agent against hypertriglyceridaemia without hepatic side‐effects.     

Impact of short‐term low‐dose atorvastatin on low‐density lipoprotein and high‐density lipoprotein subfraction phenotype

Statins can significantly reduce low‐density lipoprotein–cholesterol (LDL‐C) and modestly raise or not alter high‐density lipoprotein–cholesterol (HDL‐C). However, their impact on high‐density lipoprotein (HDL) and low‐density lipoprotein (LDL) subfractions has been less examined. The aim of the present study was to investigate the short‐term impact of low‐dose atorvastatin on HDL and LDL subfractions in humans. In this randomized study, data from 52 subjects were analysed. Thirty‐seven patients with atherosclerosis were randomized to treatment with atorvastatin 10 mg/day (n = 17) or 20 mg/day (n = 20) for 8 weeks, with 15 healthy subjects without therapy used as a control group. The lipid profile and lipoprotein subfractions were determined using the Lipoprint system at baseline and at 8 weeks. The data suggest that atorvastatin treatment (10 and 20 mg/day) for 8 weeks significantly decreases LDL‐C levels and reduces the cholesterol concentration of all LDL subfractions, which is accompanied by an increase of the mean LDL particle size. Although 10 mg/day atorvastatin treatment for 8 weeks had no impact on the HDL subfraction, 20 mg/day atorvastatin for 8 weeks significantly increased the cholesterol concentration of large HDL particles and decreased the cholesterol concentration of small HDL particles without changing serum HDL‐C levels in patients with atherosclerosis. Therefore, the results suggest that 20 mg/day atorvastatin treatment for 8 weeks may result in a favourable modification of the HDL subfraction phenotype in addition to its effects on the cholesterol concentration of all LDL subfractions and mean LDL particle size.     

The Effect of Genetic Polymorphisms in SLCO2B1 on the Lipid‐Lowering Efficacy of Rosuvastatin in Healthy Adults with Elevated Low‐Density Lipoprotein

Rosuvastatin is an HMG‐CoA reductase inhibitor widely used for treating hypercholesterolaemia. We investigated whether genetic polymorphisms in solute carrier organic anion transporter 2B1 (SLCO2B1) affect the lipid‐lowering effect of rosuvastatin in healthy adults with elevated low‐density lipoprotein (LDL). This study included 18 volunteers with LDL levels above 130 mg/dL. Rosuvastatin (20 mg) was administered once a day for 8 weeks. Blood samples were drawn before and after the 8‐week treatment to measure changes in lipid levels. The presence of single nucleotide polymorphisms (SNPs) of SLCO2B1 (c.935G>A and c.1457C>T), SLCO1B1 (c.521C>T, c.388A>G and c.‐11187G>A) and ABCG2 (c.421C>A) was determined by genotyping. Responses to rosuvastatin were compared between wild‐type and variant genotypes using permutation test on each polymorphism. In volunteers with SLCO2B1 c.935G>A (rs12422149) variant, rosuvastatin was less effective at lowering LDL (mean % decrease: GG 62.8% GA 50.6% AA 49.3%, p = 0.012) and apoprotein B (mean % decrease: GG 52.1% GA 42.8% AA 42.8%, p = 0.036). Regarding SLCO2B1 c.1457C>T (rs2306168) SNP, there was no significant difference between wild‐type and variant genotypes. This study demonstrated that SLCO2B1 c.935G>A (rs12422149) polymorphism influenced the lipid‐lowering effects of rosuvastatin in volunteers with hypercholesterolaemia.     

Puerarin Attenuates Carbon Tetrachloride‐Induced Liver Oxidative Stress and Hyperlipidaemia in Mouse by JNK/c‐Jun/CYP7A1 Pathway

Puerarin (PU), a natural flavonoid, has been reported to have many benefits and medicinal properties. The aim of this study was to investigate the effects of puerarin on hepatic oxidative stress and hyperlipidaemia in mice exposed to carbon tetrachloride (CCl₄). Male ICR mice were injected with CCl₄ with or without puerarin co‐administration (200 and 400 mg/kg intragastrically once‐daily) for 8 weeks. Our data showed that puerarin significantly prevented CCl₄‐induced hepatotoxicity, indicated by both diagnostic indicators of the liver damage (serum aminotransferase levels) and histopathological analysis. Puerarin decreased the thiobarbituric acid reactive substances (TBARS) and the protein carbonyl content (PCO) in the liver of CCl₄‐treated mice. Puerarin also restored the levels of reduced glutathione (GSH) and total antioxidant capacity (TAC) in the liver. Furthermore, the increase in serum cholesterol, triglycerides and low‐density lipoproteins (LDL) induced by CCl₄ was effectively suppressed by puerarin. The high‐density lipoprotein (HDL) level in the CCl₄ treatment mice was also increased by puerarin. Western blot analysis showed that puerarin remarkably inhibited hyperlipidaemia by regulating the expression of phosphorylated Jun N‐terminal kinases (JNK), phosphorylated c‐Jun protein and cholesterol 7a‐hydroxylase (CYP7A1) in the liver of CCl₄‐treated mice. Altogether, these results suggest that puerarin could protect the CCl₄‐induced liver injury and hyperlipidaemia by reducing reactive oxygen species S production, renewing the total antioxidant capacity and influencing expression of hepatic lipid biosynthesis and metabolism genes.     

(TTA)n Polymorphism in 3‐Hydroxy‐3‐Methylglutaryl‐Coenzyme A and Response to Atorvastatin in Coronary Artery Disease Patients

Abstract: 3‐Hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitors have been used clinically for lowering total and low‐density lipoprotein cholesterol. Interindividual pharmacological differences observed with this treatment have been attributed to genetic differences. The aim of this study was to assess the association in the low‐density lipoprotein cholesterol reduction by atorvastatin and (TTA)n polymorphism in the 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase gene in patients with coronary artery disease. Changes in total cholesterol levels, triglycerides, high‐sensitivity C‐reactive protein and free F₂‐isoprostanes were also evaluated. In an open study, patients received 40 mg atorvastatin daily for 8 weeks. Genotyping was done through polymerase chain reaction. The genotype distribution of the 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (TTA)n polymorphism was: >10/>10 in 22 out of 64 patients (34%), >10/10 in 14 out of 64 patients (22%) and 10/10 in 28 out of 64 patients (44%). The reduction of low‐density lipoprotein cholesterol levels by atorvastatin was not different between allelic variants (TTA)n repeat polymorphism. Reductions in high‐sensitivity C‐reactive protein were observed in atorvastatin‐treated patients with alleles >10/>10 and 10/10. Free F₂‐isoprostanes and total cholesterol were also significantly lower after treatment for all alleles, irrespective of type of polymorphism. In conclusion, the changes induced by atorvastatin treatment on low‐density lipoprotein cholesterol, total cholesterol, triglycerides, high‐sensitivity C‐reactive protein and free F₂‐isoprostane concentrations were not related to the presence of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase polymorphism (TTA)n.