细胞色素P450 2E1在脂肪性肝炎大鼠肝组织的表达及作用

目的探讨细胞色素P4502E1(CYP2E1)在脂肪性肝炎大鼠肝组织内的表达和作用。方法通过高脂饮食和逐渐增加酒精灌胃量持续16周建立Wister大鼠脂肪性肝炎动物模型,造模结束时检测模型组和正常组动物血脂、游离脂肪酸(FFA)和肝组织丙二醛(MDA)、超氧化物歧化酶(SOD)、还原性谷胱甘肽(GSH)含量;免疫组化标记检测肝组织CYP2E1表达;RT-PCR法检测CYP2E1 mRNA的水平。结果实验结束时,模型组大鼠血脂和血清FFA较正常组显著增高(P<0.01);肝组织MDA较正常组显著增高(P<0.01),而SOD和GSH较正常组明显减低(P<0.01);肝组织内CYP2E1及其基因表达较正常组显著升高(P<0.01),并与肝组织内MDA、脂肪变程度、炎症计分呈明显正相关(r值分别为0.652,0.913和0.943,P值均<0.05),与SOD、GSH呈显著负相关(r值分别为-0.916,-0.766,P<0.01)。结论脂肪性肝炎大鼠肝脏内CYP2E1呈诱导表达状态,后者可能通过增强氧应激,降低抗氧化能力,加重脂质过氧化等过程参与了脂肪性肝炎的形成。     

Depressed hepatic glutathione and increased diene conjugates in alcoholic liver disease

The role of lipid peroxidation in the pathogenesis of alcoholic liver disease has been a subject of controversy. In order to study this question we measured hepatic glutathione and diene conjugates in liver biopsies from 16 alcoholics with different stages of liver injury and 8 nonalcoholics with liver disease. Patients with alcoholic liver disease were found to have decreased hepatic glutathione compared to patients with liver disease unrelated to alcohol (22.1±2.5 vs 33.5±4.6 nmol/mg protein,P<0.05). The decrease in glutathione was accompanied by an increase in diene conjugates in hepatic lipids (3.37±0.14 vs 2.26±0.21 OD at 232 nm/mg lipid,P<0.001). The changes were present in all stages of alcoholic liver damage including fatty liver but unrelated to nutritional status in these patients. They support the concept that lipid peroxidation may be an important mechanism in the pathogenesis of alcoholic liver disease.     

Hepatic microsomal function in rats with chronic dietary iron overload

We determined whether alterations in hepatic microsomal function occur in association with iron-induced lipid peroxidation in vivo in rats with chronic dietary iron overload. In rats fed a 2.0% carbonyl iron diet for a period of 20 wk, there was no significant microsomal conjugated diene formation (evidence of microsomal lipid peroxidation) or difference in cytochrome P450 concentration found at mean (+/- SEM) hepatic iron concentrations of 1210 +/- 92 micrograms/g liver (wet wt) or 2730 +/- 100 micrograms/g. At a hepatic iron concentration of 4090 +/- 245 micrograms/g, however, there was significant conjugated diene formation (p less than 0.001) and a 56% decrease in the cytochrome P450 concentration (p less than 0.001). In rats fed a 2.5% carbonyl iron diet for 10 wk, achieving a liver iron concentration of 4820 +/- 420 micrograms/g, there was significant microsomal conjugated diene formation (p less than 0.001), a 35% reduction in cytochrome P450 (p less than 0.005), and a 16% reduction in aminopyrine demethylase activity (p less than 0.025), but only an 8% reduction in glucose-6-phosphatase activity (p = not significant). Finally, in rats fed a 3.0% iron-supplemented diet for 7 wk, achieving a liver iron concentration of 2730 +/- 205 micrograms/g, there was a 23% reduction in cytochrome P450 (p less than 0.025), a 28% reduction in cytochrome b5 (p less than 0.001), and a 47% increase in heme oxygenase activity (p less than 0.025) (heme oxygenase activity measured in this group only). We conclude that oral iron loading can produce microsomal lipid peroxidation in vivo that is associated with selective decreases in microsomal hemoprotein concentrations and cytochrome P450-dependent enzymes.     

Lipid peroxidation as a component in trypanocidal drug action

A representative range of trypanocides was examined for ability to induce lipid peroxidation in Trypanosoma rhodesiense in vitro. Because of drug interference, thiobarbituric acid (TBA) chromogen production and diene conjugation U.V. absorbance assay methods were less satisfactory that GLC analysis of polyenoic fatty acid loss. Docosohexanoic acid (22:6) content was specifically reduced to a highly significant degree by treatment with Ethidium or the lipid-soluble 4-demethoxydaunorubicin.     

Lack of evidence for increased lipid peroxidation in ethanol-induced centrilobular necrosis of rat liver

The pathogenetic role of lipid peroxidation in ethanol-induced liver injury was previously supported by demonstration of increased formation of diene conjugates and decreased hepatic levels of reduced glutathione in ethanol-fed animals and alcoholic patients with liver injury. The present study was carried out to investigate whether these findings can be extended to a rat model that was shown to produce a spontaneous ethanol-induced liver injury progressing from steatosis to necrosis and fibrosis (Hepatology 6: 814, 1986). Despite the histological evidence of progression from hepatic steatosis to centrilobular necrosis in these animals, diene conjugate formation in mitochondrial and microsomal lipids was not enhanced when compared to pair-fed controls. In addition, hepatic levels of neither methionine nor glutathione were decreased in the ethanol-fed animals. The fatty acid composition of mitochondrial phospholipids from these animals was similar to that in the controls. However, in the microsomal phospholipids, the level of arachidonate (20:4) was depressed by about 50% as compared to the controls. These results demonstrate the lack of evidence for a pathogenetic relationship between lipid peroxidation and ethanol-induced liver injury progressing to centrilobular necrosis. They further suggest that the decreased levels of 20:4 commonly seen after chronic ethanol intake may not be due to a peroxidative loss.     

Chronic ethanol administration induces oxidative alterations and functional impairment of pancreatic mitochondria in the rat.

Pancreas is known to be vulnerable to ethanol (ETOH) at high doses, but little is known about the effect of lower doses. Therefore, in this study, the levels of glutathione (GSH), sulfhydryl proteins (P-SH), carbonyl proteins, malondialdehyde (MDA), and adenosine triphosphate (ATP) production were determined in the pancreatic tissue and mitochondria of rats fed for 8 weeks with 3% ETOH. ETOH decreased the pancreatic pool of ATP, while GSH and P-SH also decreased in mitochondria. MDA concentrations increased both in the pancreas and mitochondria, while carbonyl proteins increased only in mitochondria. Pancreatic cells of ETOH-treated rats were frequently affected by cytoplasmic vacuolization and swelling; these alterations were often associated with ductular dilatation. In conclusion, ETOH produces oxidative and morphologic alterations in the pancreas of the rat, including impairment of mitochondria. These effects may represent basic mechanisms of ETOH-induced pancreatic injury.     

Myocardial lipid peroxidation in rats after chronic alcohol ingestion and the effects of different antioxidants

The effects of chronic intake of dietary alcohol on myocardial peroxidation (measured as formation of diene conjugates), reduced glutathione content, and morphology and the protective actions of different antioxidant compounds (vitamin E and (+)-cyanidanol-3) were studied in rats. Alcohol, comprising more than 30% of the dietary calorie content, was administered to rats for six weeks. Compared with the controls, the left ventricle of the alcoholic animals had an increased diene conjugate content (5.4(0.5) vs 4.3(0.6) optical density X g wet weight-1) and a slightly, but not significantly, decreased glutathione content (1.62(0.05) vs 1.66(0.07) mumol X g wet weight-1). Simultaneous administration of antioxidants (vitamin E or (+)-cyanidanol-3) prevented the pathological changes in diene conjugates and significantly increased the glutathione content compared with the alcoholic rats. Electron microscopy showed remarkably few ultrastructural abnormalities in the myocardium of alcoholic animals fixed by vascular perfusion. The data are consistent with the hypothesis that reactive oxygen radicals are involved in the ethanol induced biochemical changes and that the antioxidants could prevent the increased formation of peroxides in the myocardium.     

Influence of alpha-lipoic acid on lipid peroxidation and antioxidant defence system in blood of insulin-resistant rats

Background: High fructose feeding induces insulin resistance and hyperinsulinaemia in rats. A role for oxidative stress in the occurrence of insulin resistance has been suggested by several workers. Aim: The aim of this study was to investigate the effect of α‐lipoic acid (LA) on oxidant–antioxidant balance in rats fed on a high‐fructose diet that showed characteristic features of insulin resistance. Methods: Male Wistar rats weighing 150–170 g were divided into seven groups. The control group received the control diet containing starch. The fructose group was given a high‐fructose diet (>60% of total calories). The third and fourth groups were given fructose diet and were administered two different doses of LA at a low dose (35 mg/kg body weight) and high dose (70 mg/kg body weight) using olive oil as vehicle. The fifth group received fructose diet and olive oil. The sixth group received control diet and was administered LA (70 mg/kg body weight). And, the seventh group received the control diet and olive oil. Products of lipid peroxidation and activities of enzymic antioxidants, namely superoxide dismutase, catalase, glutathione peroxidase, glutathione‐S‐transferase and glutathione reductase, in red blood cells were assayed. Levels of non‐enzymic antioxidants α‐tocopherol, ascorbic acid and reduced glutathione were determined in plasma. Results: The levels of lipid peroxides, diene conjugates and thiobarbituric acid‐reactive substances were significantly higher in fructose‐fed rats. Inadequate antioxidant system was observed in high‐fructose‐fed rats. Treatment of fructose rats mitigated the imbalance between peroxidation and antioxidant defence system at both the doses tested. Increases in glucose, triglycerides, free fatty acids, insulin and insulin resistance were observed in fructose‐fed rats. LA administration prevented these alterations and improved insulin sensitivity. Significant positive correlations were obtained between insulin resistance and lipid peroxidation indices. Conclusions: Increased lipid peroxidation and deficient antioxidant system are observed in high‐fructose‐fed rats. LA administration preserves the antioxidant system and lowers lipid peroxidation. The findings suggest an interrelationship between lipid peroxidation and insulin resistance.     

Increased 4-hydroxynonenal levels in experimental alcoholic liver disease: association of lipid peroxidation with liver fibrogenesis.

The precise role of lipid peroxidation in the pathogenesis of alcoholic liver disease is still being debated. To explore the issue, this study was undertaken to investigate the status of lipid peroxidation, antioxidants and prooxidants at two discrete stages of experimental alcoholic liver disease. Male Wistar rats were intragastrically fed a high-fat diet plus ethanol for 5 or 16 wk (the duration that resulted in initiation of centrilobular liver necrosis or liver fibrosis, respectively). Lipid peroxidation was assessed in isolated microsomes and mitochondria with three parameters: malondialdehyde equivalents as determined by thiobarbituric acid assay, conjugated diene formation and 4-hydroxynonenal as a 2,4-dinitrophenylhydrazone derivative. To assess antioxidant systems, hepatic concentrations of glutathione, methionine and alpha-tocopherol were determined. The concentration of nonheme iron, a known prooxidant, was also measured. At wk 5, centrilobular liver necrosis was already evident in the ethanol-fed animals, with two- or threefold increases in plasma AST and ALT levels. At this stage, neither malondialdehyde equivalents nor conjugated diene values were elevated, and the 4-hydroxynonemal level was below 0.2 nmol/mg protein. Hepatic concentrations of methionine and alpha-tocopherol in these animals were increased two- and threefold, respectively, whereas the reduced glutathione level remained unchanged. When alcoholic liver disease had progressed to perivenular or bridging fibrosis at wk 16, all three parameters of lipid peroxidation showed consistent increases that were accompanied by significant reductions in the hepatic glutathione and methionine levels. Interestingly, the control animals pair-fed with the high-fat diet also had significantly elevated 4-hydroxynonenal levels at wk 16 compared to the wk 5 level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Iron-catalyzed lipid peroxidation in aortic cells in vitro: protective effect of extracellular magnesium

Low serum Mg2+ has been associated with an increased incidence of cardiovascular pathology in human populations. We investigated the effect of extracellular Mg2+ on Fe-catalyzed lipid peroxidation in rat aortic segments and in human aortic smooth muscle cells. Products of phospholipid oxidation [malonaldehyde (MDA) and 4-hydroxyalkenals (4-HA)], loss of fatty acyl double bonds (by proton-NMR) and glutathione levels indicated that exogenous ferric ions were several-fold more effective than ferrous ions in causing lipid peroxidation. Increased peroxidation was detectable at <1.0 microM Fe3+. Exogenous ferric iron-ionophore, 8-hydroxyquinoline, did not increase peroxidation by ferric ion, suggesting that Fe-catalyzed lipid peroxidation occurred at the cell surface. As ionized serum [Mg2+](o) was lowered from the physiological (0.7-0.96 mM) into the pathophysiological range (0.3-0.5mM) in Fe3+-containing medium, MDA/4-HA levels increased two to three-fold, with a concomitant loss of fatty acyl double bonds and decreased extracellular glutathione. Conversely, MDA/4-HA decreased as ionized Mg2+ was increased, accompanied by a rise in extracellular glutathione. The results indicate that Mg2+ protects aortic cell plasma membranes from ferric iron-catalyzed lipid peroxidation and that this is a contributing factor in the protective action of ionized Mg2+ on the cardiovascular system.     

Effects of prenatal alcohol exposure on glucose tolerance in the rat offspring

Low birth weight in humans predisposes to obesity, cardiovascular diseases, and type 2 diabetes in adult life. Alcohol exposure during pregnancy has been associated with fetal growth restriction. We investigated the effects of prenatal exposure to alcohol on glucose metabolism later in the offspring. Female Sprague Dawley rats were given ethanol (ETOH), 4 g/kg/day by gavage throughout pregnancy. Compared with controls, newborn ETOH rats had decreased body size (5.1 +/- 0.1 v 6.3 +/- 0.1 g, P <.001), plasma insulin (0.44 +/- 0.4 v 0.67 +/- 0.1 ng/mL, P <.05), and leptin mRNA (P <.05), but they had normal beta-cell mass and elevated adipose resistin mRNA and plasma glucose (5.0 +/- 0.5 v 3.6 +/- 0.3 mmol/L, P <.01). Food intake was decreased in ETOH rats during the fourth week of life, and body weight remained decreased compared with controls until a catch-up growth occurred by 7 weeks of life. At 13 weeks of age, body weight and beta-cell mass of ETOH offspring were normal, but plasma glucose and insulin after a glucose challenge were increased compared with controls (P <.05). Adipose leptin and hypothalamic Ob-R mRNA were not different from controls, but resistin was increased (P <.05), and muscle GLUT4 content was decreased (P <.05) in ETOH offspring compared with controls. The data suggest that prenatal alcohol exposure impairs glucose tolerance in the offspring by both inducing insulin resistance and beta-cell dysfunction. The prevailing mechanism in 3-month-old rat offspring appears to be insulin resistance, manifested by glucose intolerance and decreased GLUT4 despite hyperinsulinemia.     

Superoxide Dismutase, Glutathione Peroxidase, Catalase and Lipid Peroxidation of Normal and Sickled Erythrocytes

Sickled erythrocytes showed reduced glutathione peroxidase and catalase activities in comparison to normal erythrocytes. In addition, increased levels of superoxide dismutase and 'peroxidation potential'as well as fluorescent lipid pigments and malonaldehyde suggestive of membrane lipid peroxidation were found in sickled erythrocytes. Finally, sickled erythrocytes showed membrane 'bound'Heinz bodies as well as reduced membrane lipids and unsaturated fatty acids. From these observations, it is suggested that membrane lipid peroxidation occurs in sickled cells.     

脂肪肝大鼠线粒体膜流动性改变及活血化瘀法防治的实验研究

目的:探讨脂肪肝大鼠线粒体膜流动性改变及活血化瘀法的防治作用.方法:采用高脂饲料辅以乙醇和CCl4复制脂肪肝大鼠模型,观察大鼠肝脏线粒体膜的流动性,肝组织中SOD、MDA含量及肝脂,血清肝功能,血脂等变化,并以活血化瘀法进行防治,观察其对上述指标的影响.结果:模型组肝线粒体膜流动性、SOD活性明显降低、而肝组织MDA含量、肝脂及血清ALT、AST、TG、TC显著升高,与正常组比较差异有显著性意义(P＜0.01);活血化瘀法能明显改善肝线粒体膜流动性,增强SOD活性,降低血脂、肝脂、MDA含量,改善肝功能(P＜0.05或P＜0.01).结论:脂肪肝大鼠肝脏脂质过氧化增强,线粒体膜流动性降低;活血化瘀法可通过减轻肝脏脂质过氧化并修复线粒体膜流动性,从而达到减轻肝脂变、保护肝功能的作用.     

Protective effect of N-acetyl-serotonin on the nonenzymatic lipid peroxidation in rat testicular microsomes and mitochondria

N-acetyl-serotonin, the immediate precursor of melatonin in the tryptophan metabolic pathway in the pineal gland, has been reported to be an antioxidant. The aim of this study was to test the in vitro protective effect of N-acetyl-serotonin on the ascorbate-Fe(++) induced lipid peroxidation of polyunsaturated fatty acids (PUFAs) located in testis microsomes and mitochondria. We assayed increasing concentrations (0-10 mM) of N-acetyl-serotonin in testis microsomes and (0-1 mM) of N-acetyl-serotonin in testis mitochondria. Control experiments were performed by incubating microsomal and mitochondrial membranes with N-acetyl-serotonin in the absence of lipid peroxidation-inducing drugs. Special attention was paid to the changes produced on the highly PUFAs C20:4 n6 and C22:5 n6. The light emission (chemiluminescence) used as a marker of lipid peroxidation was similar in both organelles when the control and peroxidized groups were compared. N-acetyl-serotonin reduced lipid peroxidation in testicular microsomes or mitochondria for both C20:4 n6 and C22:5 n6. Both long chain PUFAs were protected when N-acetyl-serotonin was incorporated either into microsomes or mitochondria. The N-acetyl-serotonin concentration required to inhibit by approximately 70% lipid peroxidation process was 10 mM in microsomes and between 0.50 and 1 mM in mitochondria. IC 50 values calculated from the inhibition curve of N-acetyl-serotonin on the chemiluminescence rates were higher in microsomes (4.50 mM) than in mitochondria (0.25 mM). In these experimental conditions, N-acetyl-serotonin was about 18 times more potent in testicular mitochondria in inhibiting the oxidative processes than it was in testicular microsomes. These results suggest that the protective role of N-acetyl-serotonin in preserving the long PUFAs may be related to its ability to reduce lipid peroxidation.     

Melatonin protects fetal rat brain against oxidative mitochondrial damage

Our objective was to investigate the effects of melatonin on the free radical-induced oxidative damage to mitochondria in fetal rat brain. Female Wistar rats on day 19 of pregnancy were used. Melatonin (10 mg/kg) or vehicle (control) was injected intraperitoneally 60 min prior to laparotomy for removal of the fetuses. The mitochondrial fraction was isolated from the fetal rat brain of each group. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were measured. As indicators of mitochondrial respiratory activity, we determined the respiratory control index (RCI) and the adenosine 5-diphosphate/oxygen (ADP/O) ratio in the presence and absence of 2.5 microM hypoxanthine and 0.02 units/mL xanthine oxidase. Mitochondrial lipid peroxidation was determined by measuring the concentration of thiobarbituric acid reactive substances in fetal brain mitochondria in the presence or absence of 2.5 microM hypoxanthine, 0.02 units/mL xanthine oxidase, and 50 microM FeSO4. The free radical-induced rates of inhibition of mitochondrial RCI and the ADP/O ratio were both significantly lower in the fetal rat brains treated with melatonin compared with those of the controls (RCI, 44.25 +/- 15.02% vs. 25.18 +/- 5.86%, P < 0.01; ADP/O ratio, 50.74 +/- 23.05% vs. 13.90 +/- 7.80%, P < 0.001). The mitochondrial lipid peroxidation induced by free radicals was significantly reduced in the melatonin-treated group compared with the controls (484.2 +/- 147.2%) vs. 337.6 +/- 61.0%, P < 0.01). Pretreatment with melatonin significantly increased the activity of GSH-Px (20.35 +/- 5.27 to 28.93 +/- 11.01 mU/min mg(-1) protein, P < 0.05) in fetal rat brain mitochondria, but the activity of SOD did not change significantly. Results indicate that the administration of melatonin to the pregnant rat may prevent the free radical-induced oxidative mitochondrial damage to fetal rat brain by a direct antioxidant effect and the activation of GSH-Px.     

Effect of aminoguanidine on lipid peroxidation in streptozotocin-induced diabetic rats.

Diabetes mellitus is postulated to be associated with increased lipid peroxidation, which may contribute to vascular complications. One potential mechanism of the increased lipid peroxidation in diabetes is lipid-linked advanced glycosylation and oxidation. Aminoguanidine (AMGN), the prototype inhibitor of advanced glycosylation end product (AGE) formation, has been recently shown to prevent oxidative modification of low-density lipoprotein (LDL) in vitro at a moderate concentration. It is unknown whether AMGN may act as an antioxidant against lipid peroxidation under hyperglycemia in vivo. To investigate the in vivo effect of AMGN on lipid peroxidation in diabetes, we administered AMGN (1 g/L in drinking water) or vitamin E (400 mg/d for 5 d/wk) to streptozotocin (STZ)-induced diabetic rats for 9 weeks and measured plasma lipid hydroperoxides by ferrous oxidation with xylenol orange II (FOX method) and red blood cell (RBC) membrane malondialdehyde (MDA) and related aldehydes as thiobarbituric acid-reactive substances (TBARS). Plasma lipid hydroperoxide was higher in STZ-induced diabetic rats versus control rats (mean +/- SD, 7.53 +/- 2.03 v 5.62 +/- 0.44 micromol/L, P < .05; n = 8 to 14). RBC membrane TBARS were also higher in STZ-induced diabetic rats than in control rats (2.67 +/- 0.46 v 1.81 +/- 0.19 nmol/mL, P < .05). Plasma lipid hydroperoxide was lower in AMGN-treated (6.23 +/- 0.59 micromol/L, P < .05) and vitamin E-treated (5.29 +/- 0.27 micromol/L, P < .05) diabetic rats than in untreated diabetic rats. RBC membrane TBARS were also lower in AMGN-treated (1.93 +/- 0.12 nmol/mL, P < .05) diabetic rats than in untreated diabetic rats. There was no significant difference in plasma glucose, cholesterol, and triglyceride levels among diabetic groups. Although the mechanism(s) of action of AMGN on lipid peroxidation in vivo should be studied further, these results suggest that AMGN may have an additional beneficial effect as an antioxidant against lipid peroxidation in a prevention trial for diabetic vascular complications.     

Impairment of erythrocyte anti-oxidant defense mechanisms in hypoxemic patients

Defense mechanisms against lipid peroxidation were studied in erythrocytes from hypoxemic patients. The levels of lipid peroxides in patients erythrocytes were higher than those of control subjects (15.3 +/- 10.9 vs 7.5 +/- 3.0, p less than 0.05). The levels of reduced glutathione (GSH) decreased in erythrocytes from the patients (426 +/- 108 vs 756 +/- 201, p less than 0.01). Activities of glutathione peroxidase (GPX) and superoxide dismutase (SOD) were lower than those of control subjects (GPX; 27.6 +/- 7.1 vs 35.1 +/- 3.8, SOD; 76.6 +/- 42.9 vs 125.7 +/- 40.1, p less than 0.01). Positive correlations were observed between the levels of arterial oxygen pressures (PaO2) and the GSH concentrations, the activities of GPX and SOD, respectively. These data suggest that decreased anti-oxidant activity enhances lipid peroxidation in erythrocytes from hypoxemic patients.     

Evaluation of the Differential in Vivo Toxic Effects of Ethanol and Acetaldehyde on the Hypothalamic-Pituitary-Gonadal Axis Using 4-Methylpyrazole

4-Methylpyrarole (4-MP) blocks ethanol (ETOH) oxidation by inhibiting alcohol dehydrogenase (ADH). Because ADH has been identified and shown to be active in the testes, we examined the effect of ETOH + 4-MP in the ETOH-fed rat model. Weanling rats were divided Into four groups of 15 rats each and fed a liquid diet: group I received ETOH (5% v/v) + 4-MP (1.34 mM); group II was pair-fed the diet containing only 4-MP and isocalorically matched to group I; group III received ETOH dlet; and group IV was pair-fed isocaiorically to match group III. Using two-way analysis of variance for nonorthogonal data, the results were analyzed to examine both ETOH and 4-MP as the main treatment and to test for interaction. Both ETOH and 4-MP produced significant main treatment effects with significant interaction on liver/body ratio, testes weight expressed as per cent of normal, and plasma luteiniring hormone levels, and without interaction on plasma testosterone concentrations.     

Prevention of diet-induced fatty liver in experimental animals by the oral administration of a fatty acid bile acid conjugate (FABAC)

Fatty acid bile acid conjugates (FABACs) are a new family of synthetic molecules designed to solubilize biliary cholesterol. They were shown to prevent and dissolve cholesterol gallstones in inbred C57L/J mice fed a lithogenic, high-fat diet (HFD). In these mice, fatty liver was observed in the controls but not in the FABAC-treated ones. The present study was designed to study the effect of FABAC (arachidyl-amido-cholanoic acid) on diet-induced fatty liver in rats, hamsters, and mice. The fatty liver score (on a scale of 0-4 by light microscopy) was 4.0 in control hamsters and 0.3 in the FABAC-fed hamsters (P <.001). In mice it was 1.5 and 0.4, respectively (P <.01). The lipid/protein ratio in the liver was 1.3 +/- 0.44 (mg lipid/mg protein) in control rats and 0.66 +/- 0.04 in the FABAC group (P =.001) after 14 days. In hamsters it was 1.41 +/- 0.27 and 1.11 +/- 0.20, respectively (P =.03), after 21 days. In Imperial Charles River (ICR) mice the ratio was 0.34 +/- 0.10 and 0.17 +/- 0.07 (P =.03), respectively, after 24 days. Liver fat concentration, measured as mg lipid/g liver tissue, decreased similarly by FABAC feeding. The decrease in liver fat affected mainly the triglyceride levels. FABAC-fed animals gained weight similarly to the controls. Triglyceride absorption was unaffected by FABAC supplementation. In conclusion, oral FABAC therapy prevents/reduces the development of fatty liver in animals consuming a HFD.     

Binge ethanol exposure increases liver injury in obese rats

BACKGROUND & AIMS: The objective of this study was to address the hepatic effects of acute alcohol consumption in obesity by simulating an alcohol binge in genetically obese fa/fa rats compared with lean Fa/? rats. METHODS: Ethanol 4 g/kg or saline was administered by gavage every 12 hours for 3 days. RESULTS: Plasma alcohol levels were similar in both groups. Binge ethanol exposure caused liver injury in obese fa/fa but not in lean Fa/? rats, as assessed by alanine aminotransferase and H&E staining. Obesity impaired the antioxidant defense because basal levels of glutathione, glutamate cysteine ligase modulatory subunit, catalase, glutathione reductase, and superoxide dismutase were lower in fa/fa compared with Fa/? rats; the ethanol binge further decreased these antioxidants in fa/fa rats and also decreased glutathione peroxidase activity. Nonesterified fatty acids and lipid peroxidation were increased after ethanol treatment in fa/fa rats. Cytochrome P450 2E1 was down-regulated in fa/fa compared with Fa/? rats; however, the ethanol binge increased cytochrome P450 2E1 in both genotypes. Adenosine triphosphate decreased and uncoupling protein 2 increased in fa/fa rats treated with ethanol. 3-Nitrotyrosine protein adducts were detected only in fa/fa rats treated with ethanol, and this was accompanied by an induction of inducible nitric oxide synthase. Ethanol binge increased caspase-3 and caspase-8 activity, the expression of Fas ligand, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling in fa/fa rats. CONCLUSIONS: These data indicate that binge drinking increases apoptosis and liver injury in obese rats more than in lean controls and suggest that the injury may involve oxidative and nitrosative damage.