Carnosine and taurine treatments decreased oxidative stress and tissue damage induced by d-galactose in rat liver

d-galactose (GAL) causes aging-related changes and oxidative stress in the organism. We investigated the effect of carnosine (CAR) or taurine (TAU), having antioxidant effects, on hepatic injury and oxidative stress in GAL-treated rats. Rats received GAL (300 mg/kg; s.c.; 5 days/week) alone or together with CAR (250 mg/kg/daily; i.p.; 5 days/week) or TAU (2.5 % w/w; in rat chow) for 2 months. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and hepatic malondialdehyde (MDA), protein carbonyl (PC) and glutathione (GSH) levels and superoxide dismutase (SOD), glutathione peroxidase (GSH-0050x), and glutathione transferase (GST) activities were determined. Hepatic expressions of B cell lymphoma-2 (Bcl-2), Bax and Ki-67 were evaluated. Serum ALT, AST, hepatic MDA, and PC levels were observed to increase in GAL-treated rats. Hepatic Bax expression, but not Bcl-2, increased, Ki-67 expression decreased. GAL treatment caused decreases in GSH levels, SOD and GSH-Px activities in the liver. Hepatic mRNA expressions of SOD, but not GSH-Px, also diminished. CAR or TAU treatments caused significant decreases in serum ALT and AST activities. These treatments decreased apoptosis and increased proliferation and ameliorated histopathological findings in the livers of GAL-treated rats. Both CAR and TAU reduced MDA and PC levels and elevated GSH levels, SOD and GSH-Px (non significant in TAU?+?GAL group) activities. These treatments did not alter hepatic mRNA expressions of SOD and GSH-Px enzymes. Our results indicate that CAR and TAU restored liver prooxidant status together with histopathological amelioration in GAL-induced liver damage.     

Effect of carnosine alone or combined with α-tocopherol on hepatic steatosis and oxidative stress in fructose-induced insulin-resistant rats

A diet high in fructose (HFr) induces insulin resistance in animals. Free radicals are involved in the pathogenesis of HFr-induced insulin resistance. Carnosine (CAR) is a dipeptide with antioxidant properties. We investigated the effect of CAR alone or in combination with α-tocopherol (CAR?+?TOC) on HFr-induced insulin-resistant rats. Rats fed with HFr containing 60 % fructose received CAR (2 g/L in drinking water) with/without TOC (200 mg/kg, i.m. twice a week) for 8 weeks. Insulin resistance, serum lipids, inflammation markers, hepatic lipids, lipid peroxides, and glutathione (GSH) levels together with glutathione peroxidase (GSH-Px) and superoxide dismutase 1 (CuZnSOD; SOD1) activities and their protein expressions were measured. Hepatic histopathological examinations were performed. HFr was observed to cause insulin resistance, inflammation and hypertriglyceridemia, and increased triglyceride and lipid peroxide levels in the liver. GSH-Px activity and expression decreased, but GSH levels and SOD1 activity and expression did not alter in HFr rats. Hepatic marker enzyme activities in serum increased and marked macro- and microvesicular steatosis were seen in the liver. CAR treatment did not alter insulin resistance and hypertriglyceridemia, but it decreased steatosis and lipid peroxidation without any change in the antioxidant system of the liver. However, CAR?+?TOC treatment decreased insulin resistance, inflammation, hepatic steatosis, and lipid peroxidation and increased GSH-Px activity and expression in the liver. Our results may indicate that CAR?+?TOC treatment is more effective to decrease HFr-induced insulin resistance, inflammation, hepatic steatosis, and dysfunction and pro-oxidant status in rats than CAR alone.     

Cholesterol-rich diets have different effects on lipid peroxidation, cholesterol oxides, and antioxidant enzymes in rats and rabbits

The objective of this study was to compare the effect of cholesterol feeding of rats and rabbits. The levels of lipid peroxidation products and oxysterols in the plasma of the two species plus the antioxidant enzyme activities in the liver and erythrocytes were measured to explain their different susceptibilities to atherosclerosis. Our study showed that rats are less susceptible than are rabbits to the atherogenic effect of a cholesterol-rich diet because of differences in lipid peroxidation products as well as antioxidant enzymes activities in their livers. In rabbits, cholesterol feeding produced severe hypercholesterolemia (43-fold increase) and increased plasma and liver lipid peroxidation. Total as well as the individual oxysterol contents of 7alpha-, 7beta-hydroxycholesterol, alpha-epoxy, beta-epoxycholesterol, cholestanetriol, 7-keto, and 27-hydroxycholesterol significantly increased in the plasma of hypercholesterolemic (HC) rabbits. Erythrocyte glutathione peroxidase (GSH-Px) activity significantly decreased whereas catalase activity significantly increased in HC rabbits. In rats cholesterol feeding increased the plasma cholesterol only twofold and had no effect on plasma or liver lipid peroxidation. Only 7alpha- and 7beta-hydroxycholesterol increased and no change was observed in any of the antioxidant enzymes activity in the erythrocytes. Although cholesterol feeding caused a 10-fold increase of liver cholesterol as ester in both rats and rabbits, the antioxidant enzyme GSH-Px and catalase activities in the liver significantly increased in rats but significantly decreased in rabbits. The increase of GSH-Px and catalase activities in the liver of cholesterol fed rats could have a protective role against oxidation, thus preventing the formation of lipid peroxidation and oxysterols.     

富硒大豆多肽对高脂致大鼠脂肪肝和抗氧化功能的影响

目的：探讨富硒大豆多肽改善高脂所致脂肪肝大鼠肝抗氧化功能的影响及机制。方法：将40只Wistar大鼠分成4组（n=10）,分别饲喂标准饲料＋水（NC）、标准饲料＋富硒大豆多肽液（SeN）、高脂饲料＋水（HC）、高脂饲料＋富硒大豆多肽液（SeH）,10周后处死,用苏丹Ⅲ染色肝脏组织切片观察脂肪变性程度,免疫组织化学方法测定肝组织葡萄糖调节蛋白78（GRP78）表达情况,并分析其肝功能、血脂及血清和肝匀浆中谷胱甘肽过氧化物酶（GSH-Px）、超氧化物歧化酶（SOD）活性和丙二醛（MDA）含量的变化情况。结果：HC组在血清TC、TG水平、肝脏脂肪化程度、GRP78表达情况都明显高于NC、SeN、SeH组（P〈0.01）。SeH组血清和肝组织中MDA含量较HC组降低（P〈0.01）,GSH-Px、SOD活性升高。NC和SeN两组各项指标之间无明显差异。结论：富硒大豆多肽能有效提高脂肪肝大鼠肝内抗氧化酶活性,抑制脂质过氧化反应,降低肝组织内GRP78表达。     

Antihypercholesterolemic and antioxidative effects of an extract of the oyster mushroom, Pleurotus ostreatus, and its major constituent, chrysin, in Triton WR-1339-induced hypercholesterolemic rats

Hypercholesterolemia and oxidative stress are known to accelerate coronary artery disease and progression of atherosclerotic lesions. In the present study, an attempt was made to evaluate the putative antihypercholesterolemic and antioxidative effects of an ethanolic extract of the oyster mushroom (Pleurotus ostreatus) and chrysin, one of its major components, in hypercholesterolemic rats. Hypercholesterolemia was induced in rats by a single intraperitoneal injection of Triton WR-1339 (300 mg/kg body weight (b.wt.)), which resulted in persistently elevated blood/serum levels of glucose, lipid profile parameters (total cholesterol, triglycerides, low-density lipoprotein-, and very low-density lipoprotein-cholesterol), and of hepatic marker enzymes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase). In addition, lowered mean activities of hepatic antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) and lowered mean levels of nonenzymatic antioxidants (reduced glutathione, vitamin C, and vitamin E) were observed. Oral administration of the mushroom extract (500 mg/kg b.wt.) and chrysin (200 mg/kg b.wt.) to hypercholesterolemic rats for 7 days resulted in a significant decrease in mean blood/serum levels of glucose, lipid profile parameters, and hepatic marker enzymes and a concomitant increase in enzymatic and nonenzymatic antioxidant parameters. The hypercholesterolemia-ameliorating effect was more pronounced in chrysin-treated rats than in extract-treated rats, being almost as effective as that of the standard lipid-lowering drug, lovastatin (10 mg/kg b.wt.). These results suggest that chrysin, a major component of the oyster mushroom extract, may protect against the hypercholesterolemia and elevated serum hepatic marker enzyme levels induced in rats injected with Triton WR-1339.     

Apple Cider Vinegar Modulates Serum Lipid Profile,Erythrocyte, Kidney,and Liver Membrane Oxidative Stress in Ovariectomized Mice Fed High Cholesterol

The purpose of this study was to investigate the potentially beneficial effects of apple cider vinegar (ACV) supplementation on serum triglycerides, total cholesterol, liver and kidney membrane lipid peroxidation, and antioxidant levels in ovariectomized (OVX) mice fed high cholesterol. Four groups of ten female mice were treated as follows: Group I received no treatment and was used as control. Group II was OVX mice. Group III received ACV intragastrically (0.6 % of feed), and group IV was OVX and was treated with ACV as described for group III. The treatment was continued for 28 days, during which the mice were fed a high-cholesterol diet. The lipid peroxidation levels in erythrocyte, liver and kidney, triglycerides, total, and VLDL cholesterol levels in serum were higher in the OVX group than in groups III and IV. The levels of vitamin E in liver, the kidney and erythrocyte glutathione peroxidase (GSH-Px), and erythrocyte-reduced glutathione (GSH) were decreased in group II. The GSH-Px, vitamin C, E, and β-carotene, and the erythrocyte GSH and GSH-Px values were higher in kidney of groups III and IV, but in liver the vitamin E and β-carotene concentrations were decreased. In conclusion, ACV induced a protective effect against erythrocyte, kidney, and liver oxidative injury, and lowered the serum lipid levels in mice fed high cholesterol, suggesting that it possesses oxidative stress scavenging effects, inhibits lipid peroxidation, and increases the levels of antioxidant enzymes and vitamin.     

Phytosterols and lecithin do not have an additive effect in lowering plasma and hepatic cholesterol levels in diet-induced hypercholesterolemic rats

Both plant sterols and lecithin are used as dietary supplements for lowering blood cholesterol in Western countries. This study evaluated the possibility of an additive effect of these ingredients on the regulation of lipid concentrations and cholesterol metabolism. Male Sprague-Dawley rats were randomly divided into three groups, and fed one of the following diets for 5 weeks; high cholesterol diet (HCD), phytosterol mixture-supplemented diet (PD, HCD+0.25% phytosterols), or phytosterol mixture and lecithin-supplemented diet (PLD, PD+0.15% lecithin). Feeding the PD for 5 weeks resulted in a 34% and 41% decrease in plasma total- and VLDL+LDL-cholesterol levels, respectively, and a 23% decrease in hepatic cholesterol content compared to those for the HCD rats (p < 0.05). These cholesterol-lowering properties of the phytosterol mixture were also associated with the down-regulation of hepatic acyl CoA:cholesterol acytransferase (ACAT) activity (p < 0.05). Addition of lecithin plus phytosterol mixture to the hypercholesterolemic diet did not significantly affect blood and hepatic lipid concentrations (with the exception of 36% decrease in hepatic triglyceride level, p < 0.05) as well as hepatic ACAT activity compared to feeding the hypercholesterolemic diet supplemented with phytosterol alone. These results indicate that combining lecithin, at a 0.15% level, with a phytosterol mixture-supplemented diet does not exhibit an additive effect in regulating hepatic ACAT activity or lowering blood cholesterol in hypercholesterolemic rats.     

Effect of samh seeds supplementation (Mesembryanthemum forsskalei Hochst) on liver enzymes and lipid profiles of streptozotocin (STZ)-induced diabetic Wistar rats

Thirty streptozotocin (STZ)-induced diabetic of Wistar Albino rats were divided into five groups. The rat groups received different food (natural diet or high fat content diet) supplemented with 10% or 15% of samh seeds for 6 weeks. At the end of the study, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phophatase (ALP) and lactate dehydrogenase (LDH) enzymes have been measured in diabetic rats liver. In addition, liver lipid profile (total cholesterol (TC), triglyceride (TAG), lipid peroxide production malondialdehyde (MDA)) and reduced glutathione (GSH) in have been measured in diabetic rats liver, and the levels of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) were also determined. The samh seeds diet supplemented with cholesterol significantly increase (P < 0.05) the levels of liver peroxide production MDA, TC and TG in diabetic rats comparing to the samh diet not supplemented with the cholesterol. However, the samh seeds significantly decrease (P < 0.05) the level of GSH. These data suggest that the samh seeds diet not supplemented with the cholesterol regulated C and TG metabolism and decrease the lipid peroxidation in the diabetic rats.     

Antidiabetic Activity of a Lotus Leaf Selenium (Se)-Polysaccharide in Rats with Gestational Diabetes Mellitus

A selenium (Se)-containing polysaccharide, lotus leaf selenium (Se)-polysaccharide (LLP), was isolated from a lotus leaf. The effects of LLP on antioxidant enzyme activities and insulin resistance in pregnant rats with gestational diabetes mellitus (GDM) were investigated. LLP administered orally at two doses (50 and 100 mg/kg) could significantly reverse the weight loss of pregnant rats before the delivery, fetal rats, and placentas in GDM rats (P < 0.05). Furthermore, LLP treatment induced a decrease of fasting blood glucose (FBG) and fasting blood insulin (FINS) levels in GDM rats, but an increase of hepatic glycogen content, when compared with those in GDM rats (P < 0.05). Also, oral administrations of LLP markedly improved the lipid profile of GDM rats, as evidenced by a reduction of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) cholesterol levels except for the high-density lipoprotein (HDL) cholesterol level. Additionally, antioxidant enzyme levels, such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione (GSH), in liver tissues of the GDM group were lower than those of the other groups, and following treatment of LLP, these indexes in liver tissues were equivalent to those of the control group (P > 0.05). All the data indicated that LLP may be a promising drug candidate or a healthcare food for GDM therapy or protection.     

Hazelnut oil administration reduces aortic cholesterol accumulation and lipid peroxides in the plasma, liver, and aorta of rabbits fed a high-cholesterol diet

Hazelnut oil (HO) is rich in monounsaturated fatty acids and antioxidants. We wanted to investigate the effect of HO on lipid levels and prooxidant-antioxidant status in rabbits fed a high-cholesterol (HC) diet. An HC diet caused significant increases in lipids and lipid peroxide levels in the plasma, liver, and aorta together with histopathological atherosclerotic changes in the aorta. Glutathione levels, glutathione peroxidase, and glutathione transferase activities decreased significantly, but superoxide dismutase activity and vitamin E and C levels remained unchanged in the livers of rabbits following HC diet. HO supplementation reduced plasma, liver, and aorta lipid peroxide levels and aorta cholesterol levels together with amelioration in atherosclerotic lesions in the aortas of rabbits fed an HC diet, without any decreasing effect on cholesterol levels in the plasma or liver. HO did not alter the antioxidant system in the liver in the HC group. Our findings indicate that HO reduced oxidative stress and cholesterol accumulation in the aortas of rabbits fed an HC diet.     

Hypolipidemic effect of the edible mushroom Agaricus blazei in rats subjected to a hypercholesterolemic diet

The effects of Agaricus blazei intake on the lipid profile of animals fed a hypercholesterolemic diet were evaluated. Thirty-two female Fisher rats were divided into four groups and given the standard AIN-93 M diet (C), this diet?+?1 % A. blazei (CAb), a hypercholesterolemic diet with 25 % soybean oil and 1 % cholesterol (H) or this diet?+?1 % A. blazei (HAb) for 6 weeks. Food intake, weight gain, liver and serum lipid profiles, activity of aminotransferases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)], and creatinine and urea levels as well as abdominal fat weight were measured. Histological analysis of kidney and liver tissue was also performed. The HAb group had a higher food intake, but a lower weight gain as compared to group H. This resulted in a significant decrease in abdominal fat weight, to values close to those of groups C and CAb. Supplementing the hypercholesterolemic diet with A. blazei promoted a significant reduction in total and non-HDL cholesterol, as well as in the atherogenic index, as compared to group H, and this effect was more pronounced in the serum. There was no hepatotoxic effect caused by the supplementation of the diets with the mushroom. We conclude that in our experimental model and in the concentration used, A. blazei was effective in improving the lipid profile of the animals.     

Dietary taurine enhances cholesterol degradation and reduces serum and liver cholesterol concentrations in rats fed a high-cholesterol diet

Summary.  The effect of taurine on hypercholesterolemia induced by feeding a high-cholesterol (HC) diet (10 g/kg) to rats was examined. When taurine was supplemented to HC for 2 wk, serum total cholesterol significantly decreased and serum HDL-cholesterol increased compared with the HC diet group. In the hypercholesterolemic rats fed the HC diet, the excretion of fecal bile acids and hepatic cholesterol 7α-hydroxylase (CYP7A1) activity and its mRNA level increased significantly, and the supplementation of taurine further enhanced these indexes, indicating an increase in cholesterol degradation. Agarose gel electrophoresis revealed that, in hypercholesterolemic rats fed the HC diet, the serum level of the heavier VLDL increased significantly, but taurine repressed this increase and normalized this pattern. Significant correlations were observed between the time-dependent increase of CYP7A1 gene expression and the decrease of blood cholesterol concentration in rats fed the HC diet supplemented with taurine. These results suggest that the hypocholesterolemic effects of taurine observed in the hypocholesterolemic rats fed the HC diet were mainly due to the enhancement of cholesterol degradation and the excretion of bile acid. Received December 4, 2001 Accepted January 2, 2002 Published online September 10, 2002 Acknowledgment This work was supported by a grant of Taisho Pharmaceutical Co., Ltd (Japan). We thank J. I. Gordon for their generous gifts of cDNAs. Authors' address: Dr. Hidehiko Yokogoshi, School of Food and Nutritional Sciences, The University of Shizuoka, Shizuoka 4228526, Japan, E-mail: yokogosi@u-shizuoka-ken.ac.jp     

Changes in antioxidant defense status in hypercholesterolemic rats treated with Ajuga iva

The aim of the study was to investigate the effect of aqueous extract of Ajuga iva (Ai) on serum and tissues lipid peroxidation as well as antioxidant enzymes activities in red blood cells (RBC) and tissues, in high hypercholesterolemic rats (HC). Male Wistar rats (n=12) were fed on 1% cholesterol-enriched diet for 15 d. After this adaptation phase, hypercholesterolemic rats (total cholesterol=6.5±0.6 mol/l) were divided into two groups fed the same diet and treated or not with Ai for 15 d. Thiobarbituric acid reactive substances (TBARS) concentrations in serum, LDL-HDL₁, HDL₂ and HDL₃ were respectively, 5-, 7.8-, 2.3- and 5-fold lower in Ai treated than untreated hypercholesterolemic groups. TBARS concentrations were 1.4-fold lower in heart and 2.8-fold higher in kidney in Ai-HC treated than untreated HC group. Superoxide dismutase activity was respectively, 1.2- and 1.4-fold higher in RBC and muscle in Ai treated than untreated group. In RBC, Ajuga iva treatment enhanced glutathione peroxidase (GSH-Px) (+9%) and glutathione reductase (GSSH-Red) (+12%) in Ai-HC treated than untreated HC group. GSSH-Red activity was 1.4- and 1.5-fold higher in adipose tissue and heart, respectively and 3.7-fold lower in kidney in Ai treated than untreated group. Liver catalase activity was 1.6-fold higher in Ai treated than untreated group. Adipose tissue and muscle total glutathione content represented in Ai treated group 35% and 36% of the value noted in untreated group. Nitric oxide values of liver, adipose tissue and heart were 3.3-, 2.5- and 3.4-fold higher in Ai-HC than HC group. Ajuga iva treatment enhanced α-tocopherol contents (+25%) in Ai treated than untreated group. In conclusion, Ajuga iva treatment is more effective to improve the antioxidant capacity of RBC than that of tissues. Indeed, Ai is able to reduce the oxidative stress in hypercholesterolemic rats by increasing the antioxidant enzymes activity.     

有氧运动对高胆固醇血症大鼠肝脏低密度脂蛋白受体活性调节…

本文研究了实验性在醇血症大鼠肝脏低密度脂蛋白受体（ＬＤＬ－Ｒ）活性变化及有氧运动时ＬＤＬ－Ｒ活性调节的影响,发现,高脂（ＨＣ）组肝组织匀浆ＬＤＬ－ＲＩ自古以来生较正常对照（ＮＣ）组降低３７％（Ｐ〈０．０５）,同时血清大醇（ＴＣ）、低密度脂收白胆固醇（ＬＤＬ－Ｃ）及血清栽脂蛋白Ｂ（ＡｐｏＢ）均显著高于ＮＣ组（Ｐ〈０．０１）;高脂＋运动（ＨＥ）组ＴＣ、ＬＤＬ－Ｃ及ＡｐｏＢ均明显低于ＨＣ组,而ＬＤＬ－Ｒ     

Evaluation of the anti-atherogenic potential of chrysin in Wistar rats

Hypercholesterolemia is one of the major risk factors that precipitate coronary heart disease and atherosclerosis. Oxidative stress is believed to contribute to the pathogenesis of hypercholesterolemic atherosclerosis; hence, various antioxidant compounds are being evaluated for potential anti-atherogenic effects. In the present study, the putative anti-atherogenic and antioxidant efficacy of a flavonoid, chrysin, was evaluated in an experimental model of atherosclerosis. In male, albino Wistar rats fed an atherogenic diet for 45 days and treated with saline, significantly higher mean levels of serum lipid profile parameters (total cholesterol, triglycerides, low-density, and very low-density lipoprotein cholesterol), lower mean levels of high-density lipoprotein cholesterol and higher mean serum levels of hepatic marker enzymes (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase) were observed when compared with the levels in rats fed a control diet. In addition, significantly lower mean hepatic levels of lipoprotein lipase, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) and non-enzymatic antioxidants (reduced glutathione, and vitamins C and E), and a significantly higher mean level of hepatic malondialdehyde (MDA) were noted in comparison to the values in control rats. In atherogenic diet-fed rats that received chrysin orally (200 mg/kg b.wt) for 15 days, starting 30 days after the start of the atherogenic diet, significantly lower mean serum levels of lipid profile parameters (except for HDL-cholesterol which was elevated), hepatic marker enzymes, and significantly higher mean hepatic levels of LPL, HMG-CoA reductase, enzymatic, and non-enzymatic antioxidants and significantly lower mean levels of hepatic MDA were noted, compared to the values in atherogenic diet-fed, saline-treated rats. Histopathological studies appeared to suggest the protective effect of chrysin on the hepatic tissue and aorta of atherosclerotic rats. These results suggest that chrysin has anti-atherogenic potential in an experimental setting.     

Insulin dysregulation drives mitochondrial cholesterol metabolite accumulation: initiating hepatic toxicity in nonalcoholic fatty liver disease

CYP7B1 catalyzes mitochondria-derived cholesterol metabolites such as (25R)26-hydroxycholesterol (26HC) and 3β-hydroxy-5-cholesten-(25R)26-oic acid (3βHCA) and facilitates their conversion to bile acids. Disruption of 26HC/3βHCA metabolism in the absence of CYP7B1 leads to neonatal liver failure. Disrupted 26HC/3βHCA metabolism with reduced hepatic CYP7B1 expression is also found in nonalcoholic steatohepatitis (NASH). The current study aimed to understand the regulatory mechanism of mitochondrial cholesterol metabolites and their contribution to onset of NASH. We used Cyp7b1^−/− mice fed a normal diet (ND), Western diet (WD), or high-cholesterol diet (HCD). Serum and liver cholesterol metabolites as well as hepatic gene expressions were comprehensively analyzed. Interestingly, 26HC/3βHCA levels were maintained at basal levels in ND-fed Cyp7b1^−/− mice livers by the reduced cholesterol transport to mitochondria, and the upregulated glucuronidation and sulfation. However, WD-fed Cyp7b1^−/− mice developed insulin resistance (IR) with subsequent 26HC/3βHCA accumulation due to overwhelmed glucuronidation/sulfation with facilitated mitochondrial cholesterol transport. Meanwhile, Cyp7b1^−/− mice fed an HCD did not develop IR or subsequent evidence of liver toxicity. HCD-fed mice livers revealed marked cholesterol accumulation but no 26HC/3βHCA accumulation. The results suggest 26HC/3βHCA-induced cytotoxicity occurs when increased cholesterol transport into mitochondria is coupled to decreased 26HC/3βHCA metabolism driven with IR. Supportive evidence for cholesterol metabolite-driven hepatotoxicity is provided in a diet-induced nonalcoholic fatty liver mouse model and by human specimen analyses. This study uncovers an insulin-mediated regulatory pathway that drives the formation and accumulation of toxic cholesterol metabolites within the hepatocyte mitochondria, mechanistically connecting IR to cholesterol metabolite-induced hepatocyte toxicity which drives nonalcoholic fatty liver disease.     

有氧运动对高胆固醇血症大鼠肝脏低密度脂蛋白受体活性调节的影响

本文研究了实验性高胆固醇血症大鼠肝脏低密度脂蛋白受体（ＬＤＬＲ）活性变化及有氧运动时ＬＤＬＲ活性调节的影响。发现,高脂（ＨＣ）组肝组织匀浆ＬＤＬＲ活性较正常对照（ＮＣ）组降低３７％（Ｐ＜０．０５）,同时血清总胆固醇（ＴＣ）、低密度脂蛋白胆固醇（ＬＤＬＣ）及血清载脂蛋白Ｂ（ＡｐｏＢ）均显著高于ＮＣ组（Ｐ＜０．０１）;高脂＋运动（ＨＥ）组ＴＣ、ＬＤＬＣ及ＡｐｏＢ均明显低于ＨＣ组,而ＬＤＬＲ活性则较ＨＣ组增高２６％（Ｐ＜０．０５）。结果提示：（１）高胆固醇负荷时细胞可通过下行调节影响ＬＤＬＲ活性;（２）运动可能通过增加对细胞内胆固醇利用和降解,反馈作用于下行调节过程影响ＬＤＬＲ的合成,增加对ＬＤＬＣ摄取而显著改善血脂水平。     

Exercise training decreases plasma leptin levels and the expression of hepatic leptin receptor-a, -b, and, -e in rats

In addition to acting in the central nervous system, leptin also acts on peripheral tissues such as liver to provide a protection against lipid accretion. Previous evidence from human and animal model indicates that exercise training reduces circulating leptin levels beyond the changes in adiposity levels. Because liver is one of the main peripheral organs for leptin action, this present study was designed to determine whether leptin receptors expression in liver is changed by exercise training. Female rats trained (TR) or kept sedentary (Sed) for 8 weeks were submitted either to a standard (SD) diet for 8 weeks or for 6 weeks followed by 2 weeks of high-fat (HF) or high-carbohydrate (HC) feeding. Food intake, adiposity levels, circulating plasma leptin and insulin concentrations along with the hepatic expression of leptin receptors (ObR-a, -b, and -e) and peroxisome proliferator-activated receptor α (PPARα) and peroxisome proliferator-activated receptor-gamma co-activator-1α (PGC-1α), were measured in all the animals. Intra-abdominal fat depots were increased under the HF but not under the HC diet. As expected, exercise training decreases intra-abdominal adiposity in animals fed with the SD and the HF diet, and to a lesser extent in HC-fed rats. Plasma leptin levels either expressed in absolute values or in values relative to adiposity levels were significantly (P < 0.05) increased with the HF diet and significantly decreased in TR animals, independently of the diet. Moreover, a significant (P < 0.01) reduction in hepatic gene expression of ObR-a, -b and -e was found in TR animals in all the three diet conditions. PPARα and PGC-1α mRNAs were also decreased (P < 0.05) in TR animals in two out of three diet conditions. The present findings indicate that exercise training-induced decrease in plasma leptin levels is accompanied by a reduction in gene expression of three different isoforms of leptin receptors in liver.     

Association between 12α-hydroxylated bile acids and hepatic steatosis in rats fed a high-fat diet

High-fat (HF) diet induces hepatic steatosis that is a risk factor for noncommunicable diseases such as obesity, type 2 diabetes and cardiovascular disease. Previously, we found that HF feeding in rats increases the excretion of fecal bile acids (BAs), specifically 12α-hydroxylated (12αOH) BAs. Although the liver is the metabolic center in our body, the association between hepatic steatosis and 12αOH BAs in HF-fed rats is unclear. Thus, we investigated extensively BA composition in HF-fed rats and evaluated the association between hepatic steatosis and 12αOH BAs. Acclimated male inbred WKAH/HkmSlc rats were divided into two groups and fed either control or HF diet for 8 weeks. Feeding HF diet increased hepatic triglyceride and total cholesterol concentrations, which correlated positively with 12αOH BAs concentrations but not with non-12αOH BAs in the feces, portal plasma and liver. Accompanied by the increase in 12αOH BAs, the rats fed HF diet showed increased fat absorption and higher mRNA expression of liver Cidea. The enhancement of 12αOH BA secretion may contribute to hepatic steatosis by the promotion of dietary fat absorption and hepatic Cidea mRNA expression. The increase in 12αOH BAs was associated with enhanced liver cholesterol 7α-hydroxylase (Cyp7a1) and sterol 12α-hydroxylase (Cyp8b1) mRNA expression. There was a significant increase in 7α-hydroxycholesterol, a precursor of BAs, in the liver of HF-fed rats. Altogether, these data suggest that the HF diet increases preferentially 12αOH BAs synthesis by utilizing the accumulated hepatic cholesterol and enhancing mRNA expression of Cyp7a1 and Cyp8b1 in the liver.     

Effects of dietary selenium and vitamin E concentrations on phospholipid hydroperoxide glutathione peroxidase expression in reproductive tissues of pubertal maturing male rats

Phospholipid hydroperoxide glutathione peroxidase (PHGPX) is the second intracellular selenium (Se)-dependent glutathione peroxidase (GSH-Px) identified in mammals. Our objectives were to determine the effect of dietary vitamin E and Se levels on PHGPX activity expression in testis, epididymis, and seminal vesicles of pubertal maturing rats, and the relationship of PHGPX expression with testicular development and sperm quality. Forty Sprague-Dawley male weanling rats (21-d old), were initially fed for 3 wk a torula yeast basal diet (containing 0.05 mg Se/kg) supplemented with marginal levels of Se (0.1 mg/kg as Na₂SeO₃) and vitamin E (25 IU/kg as all-rac-α-tocopheryl acetate). Then, rats were fed the basal diets supplemented with 0 or 0.2 mg Se/kg and 0 or 100 IU vitamin E/kg diet during the 3-wk period of pubertal maturing. Compared with the Se-supplemented rats, those fed the Se-deficient diets retained 31, 88, 67, and 50% of Se-dependent GSH-Px activities in liver, testis, epididymis, and seminal vesicles, respectively. Testes and seminal vesicles had substantially higher (5-to 20-fold) PHGPX activity than liver. Dietary Se deficiency did not affect PHGPX activities in the reproductive tissues, but reduced PHGPX activity in liver by 28% (P < 0.0001). Dietary vitamin E supplementation did not affect PHGPX activity in liver, whereas it raised PHGPX activity in seminal vesicles by 43% (P < 0.005). Neither dietary vitamin E nor Se levels affected body weight gains, reproductive organ weights, or sperm counts and morphology. In conclusion, expression of PHGPX activity in testis and seminal vesicles was high and regulated by dietary Se and vitamin E differently from that in liver.