氧化苦参碱及甘草酸对小鼠肝细胞凋亡的影响

目的：研究氧化苦参碱（OM）及甘草酸（GL）对撤除苯巴比妥钠(PB)诱导的小鼠肝细胞凋亡的影响。方法：以肝体重比、肝组织DNA含量、组织学改变及原位凋亡细胞Tunel标记为指标，观察OM150mg/kg及GL50mg/kg，腹腔注射1次／8h．对撤除PB后引起的小鼠肝细胞凋亡的影响，结果：阳性对照组肝体重比及肝DNA含量分别回落16．3％及32．4％；GL组肝体重比及肝DNA含量分别回落16．1％及28．9％；OM组肝体重比及肝DNA含量无明显回落，组织学检查及凋亡细胞Tunel标记示：阳性对照组及GL组肝细胞出现典型凋亡样改变，Tunel标记阳性；阴性对照组及OM组肝组织未见明显凋亡改变。结论：OM可阻断撤除PB诱导的小鼠肝细胞凋亡，GL对其无影响。     

经门静脉骨髓基质细胞移植治疗肝纤维化

目的: 探讨移植骨髓基质细胞(BMSCs)减轻小鼠肝纤维化的作用.方法: BALB/c小鼠BMscs分离培养及经门静脉移植到BALB/c小鼠肝脏,二乙基亚硝胺诱导肝纤维化.60只小鼠随机分为对照组.模型组及治疗组.3 mo后测定ALT、AST、透明质酸酶(HA)和层黏连蛋白(LN)浓度,及肝脏羟基脯氨酸(Hyp)含量.免疫组化检测肝脏a.平滑肌肌动蛋白(α-SMA)表达,及荧光原位杂交鉴定移植的BMSCs向肝细胞的分化.结果: BMsCs在添加肝细胞生长因子(HGF)的培养基中体外培养能分化为肝细胞样细胞.与模型组相比.移植BMscs能显著降低血清ALT、AST、HA和LN的水平以及肝脏Hyp含量和α-SMA的表达(208±44 U/L 341±66 U/L,372±84 U/L vs 506±81 U/L,289±74μg/L vs 362±83 μg/L,178±48 μg/L vs 232±63 ug/L,900±141 mg/g liver vs1255±205mg/g liver,,均p<0.01).荧光原位杂交显示DEN诱导的损伤肝脏中有骨髓来源的肝细胞,3 mo后10%的肝细胞来源于BMSCs.结论: 在肝纤维化模型中,经门静脉移植的BMscs能分化为肝细胞,有效地恢复肝功能和减轻肝纤维化.     

白藜芦醇促进肝部分切除术后肝再生的实验研究

目的研究白藜芦醇对小鼠70%肝切除后残余肝的再生是否有促进作用。方法实验动物为雄性C57BL/6小鼠。将100只小鼠随机分为实验组(白藜芦醇预处理组)和对照组(生理盐水预处理组)。采用肝大部分切除术建立肝再生模型,术前连续5 d分别给予小鼠腹腔内注射白藜芦醇12 g/kg(实验组)和生理盐水(对照组),第5天注射完白藜芦醇和生理盐水2 h后给两组小鼠分别进行70%的肝切除手术(pH)。用肝重/体重比,实时定量聚合酶链式反应及免疫组化等方法来评估白藜芦醇对小鼠肝再生的促进作用。结果 pH术后36 h、48 h实验组与对照组相比,肝重/体重比增高(4.56±0.07对3.93±0.07;5.36±0.07对4.6±0.09)。肝脏ki-67术后36 h表达最为活跃,48 h后下降,实验组与对照组相比ki-67表达明显增高。实验组中组织肝细胞生长因子(HGF)及肿瘤坏死因子(TNF-α)水平明显比对照组增强。结论白藜芦醇能明显促进小鼠部分肝切除后的肝再生。     

高山红景天对老龄小鼠过氧化脂质和脂褐素含量的影响

高山红景天为长白山珍贵滋补品,1～2g/kg高山红景天粉能明显降低14月龄小鼠血、肝和睾丸的过氧化脂质(IPO)和睾丸的脂褐素(LPF)含量,其作用优于人参粉。0.05～0.20g/kg高山红景天醇提取物可降低小鼠肝LPO和心脏LPF。说明高山红景天具有对抗自由基氧化作用。     

山楂叶总黄酮对酒精性肝损伤小鼠肝细胞凋亡的影响

目的研究山楂叶总黄酮(FMCL)对酒精性肝损伤小鼠肝细胞凋亡的影响并探讨其机制。方法昆明种小鼠60只随机分为正常组、模型组、FMCL低、高剂量组和维生素E阳性对照组。采用白酒灌胃制备急性肝损伤模型,造模同时按剂量(40、80 mg/kg)每天给予FMCL保护,10 d后处死小鼠,TUNEL法检测肝细胞凋亡情况,HE染色观察肝组织病理学变化,比色法检测肝组织丙二醛(MDA)、超氧化物歧化酶(SOD)、还原型谷胱甘肽(GSH)水平。结果和模型组比较,FMCL明显降低酒精性肝损伤小鼠肝细胞凋亡指数,TUNEL染色阳性细胞数明显减少(P0.01),肝细胞脂肪变性、炎症坏死等病理改变明显好转;模型组小鼠肝组织MDA含量明显升高,SOD、GSH活性明显降低,给予FMCL保护后,MDA含量明显降低,SOD、GSH活性明显提高(P0.05,P0.01)。结论 FMCL对酒精性肝损伤小鼠肝细胞凋亡具有一定的抑制作用,其机制与抑制酒精介导的脂质过氧化有关。     

基于MAVS介导信号通路的补肾方抗炎抗HBV作用及机制研究

目的:观察补肾方对刀豆蛋白A(ConA)诱导HBV转基因小鼠肝损伤的抗炎及抗HBV作用机制。方法:24只HBV转基因小鼠随机分为3组,模型组及补肾方组小鼠按照体重予以3μg/g ConA尾静脉注射,正常组予以相应量生理盐水,每周1次,连续4周。造模后,补肾方组小鼠予以补肾方汤剂2.25g/kg体重灌胃,正常组及模型组小鼠予以等量生理盐水,每天1次,连续4周。观察各组小鼠处理前后血清丙氨酸转移酶(ALT)、天冬氨酸转移酶(AST)、乙型肝炎病毒表面抗原(HBsAg)、乙肝肝炎病毒脱氧核糖核酸(HBV DNA)水平及肝组织病理变化,观察各组小鼠处理前后肝组织HBcAg表达及肝组织线粒体抗病毒蛋白(MAVS)介导信号通路关键蛋白表达。结果:补肾方可显著降低ConA诱导HBV转基因小鼠血清ALT、AST水平(P0.01),减轻肝组织内炎性细胞的浸润及肝细胞的变性坏死;可显著降低小鼠血清HBsAg水平(P0.05),降低肝组织内HBcAg的表达(P0.001);可显著提高小鼠血清IFN-β水平(P0.01),上调TBK-1、STING、pTAK-1(t183)的表达,下调TRADD的表达(P0.05)。结论:补肾方具有减轻肝组织炎症、抗HBV作用,其作用机制与MAVS介导的信号通路有关。     

木贼提取液对老龄小鼠抗氧化作用的影响

目的 探讨木贼提取液对老龄小鼠的抗氧化作用.方法 将32只小鼠随机分为4组,分别为木贼提取液高剂量组(8 g/kg)、中剂量组(6 g/kg)、低剂量组(4g/kg)和对照组,每组8只.四组连续灌胃21 d,1次/d,第22天处死小鼠,迅速取其心、脑、肝组织测定超氧化物歧化酶(SOD)、丙二醛(MDA)的含量.结果 木贼提取液组SOD含量除低剂量组心脏组织中升高不明显,其余三组小鼠心、脑、肝组织中SOD含量均高于对照组(P＜0.05,0.01).木贼提取液组与对照组MDA含量比较,高剂量组心脏组织中降低较为明显(P＜0.05),中、低剂量组脑组织MDA降低较明显(P＜0.05);中剂量组脏肝MDA降低较明显(P＜0.01).结论 木贼提取液具有抵抗和清除老龄小鼠体内自由基的作用,可延缓衰老进程.     

蛇床子素对四氯化碳诱导小鼠脂质过氧化反应的影响

目的:研究蛇床子素(Ost)对四氯化碳(CCl_4)诱导小鼠脂质过氧反应的影响.方法:40只昆明种小鼠随机平均分为4组:正常对照组、模型组、Ost治疗1组(50 g/kg)、Ost治疗2组(100 g/kg).除对照组外,其余各组腹腔注射1 g/L CCl_4花生油溶液.16 h后分别测定血清SOD和T-AOC及肝组织MDA,NO和T-AOC.结果:与模型组相比,50 g/kg Ost显著升高肝组织NO含量(F=6.171,P=0.01);100 g/kg Ost显著降低CCl_4中毒小鼠肝组织中MDA含量(F=3.547,P=0.04),升高NO(F=3.698,P =0.009)和T-AOC(P=0.000)以及血清中提高SOD活性(F=4.797,P=0.04)和T-AOC(F= 3.103,P=0.02).结论:蛇床子素有抗脂质过氧化作用.     

小鼠急性酒精性肝损伤模型的建立

目的:建立一次性暴饮小鼠急性酒精性肝损伤模型,并动态研究肝脏病理形态学、氧化应激因子、炎症因子的变化.方法:将48只ICR小鼠随机分成2组,空白对照组一次性给予等热量、等体积的糖水6 g/kg灌胃,模型组一次性给予50%乙醇(6 g/kg)体质量灌胃,分别于灌胃后1.5、3、6、12 h动态监测小鼠血清谷丙转氨酶(alanine aminotransferase,ALT)、甘油三酯(triglyceride,TG),肝组织匀浆丙二醛(malondialdehyde,MDA)、还原型谷胱甘肽(reduced glulathione hormone(GSH)、超氧化物歧化酶(superoxide dismutase,SOD),及肝组织白介素-1β(interleukin 1β,IL-1β)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)表达;肝组织HE染色、苏丹Ⅲ染色观察肝组织形态学、脂肪变性程度.结果:成功复制了一次性暴饮50%乙醇(6 g/kg)的小鼠急性肝损伤模型,小鼠无死亡,出现翻正反射消失、嗜睡等醉酒状态.模型组小鼠血清ALT、TG水平随时间逐渐升高,6 h达峰值,12 h略下降;肝匀浆GSH含量6 h降至最低;造模后1.5 h肝脏SOD含量下降最为显著,下降约24%;1.5 h肝脏MDA含量上升最为显著,上升至正常组的2.2倍;肝脏IL-1β、TNF-α水平升高,12 h达峰值;HE染色结果示,造模后12 h可见中央静脉及小叶间经脉周围出现肝细胞肿胀、水样变性等病理改变;苏丹Ⅲ染色结果显示随着造模时间延长肝脂肪变性程度加重.结论:此模型造模周期短、易复制、稳定性好,是研究急性酒精性肝损伤发病机制和筛选药物的理想模型.     

补阳还五汤含药血清对肝纤维化小鼠形态学和转化生长因子-β1水平的影响

目的探讨补阳还五汤含药血清(SCBHD)对肝纤维化(LF)小鼠形态学和转化生长因子(TGF)-β1的影响。方法小鼠随机分成对照组,模型组,秋水仙碱组(0.001 g/kg),SCBHD高、中、低剂量组(37.06、18.53、9.26 g/kg)。采用30%CCl4(1 ml/kg)腹腔注射诱导LF小鼠。SCBHD连续灌胃小鼠,治疗40 d后取材。放射免疫法检测小鼠血清透明质酸(HA)、层黏连蛋白(LN)、Ⅲ型前胶原(PCⅢ)和Ⅳ型胶原(CⅣ)水平。HE染色、Masson染色和透射电子显微镜(TEM)观察小鼠肝脏镜下结构、计算脾、胸腺和肝指数。采用酶联免疫吸附法(ELISA)测定肝组织TGF-β1水平。结果与模型组比较,SCBHD高、中剂量组小鼠血清HA、LN、PCⅢ和CⅣ明显降低(P<0.05),小鼠LF明显减轻,脾和胸腺指数明显升高伴有肝指数明显降低(P<0.05),肝TGF-β1含量明显降低(P<0.05)。结论 SCBHD能改善小鼠形态结构,改善脾、胸腺、肝指数,这与降低小鼠肝TGF-β1表达有关。     

垂盆草对小鼠和大鼠肝脏脂质过氧化损伤的防护作用

本实验观察了垂盆草水提物对急性酒清中毒所致小鼠肝脏脂质过氧化损伤的影响,同时又观察了垂盆草水提物对氧自由基损伤的作用。结果表明,口服垂盆草(10g/kg),无论是给药3次还是1次均能明显防止酒精所致小鼠肝脏谷胱苷肽(GSH)的耗竭及脂质过氧化产物丙二醛(MDA)的生成。垂盆草与大鼠肝微粒体体外温孵,对 NADPH—Vit C 所致微粒体脂质过氧化和 Fe_(2+)-半胱氨酸(cys)所致大鼠肝细胞的脂质过氧化损伤亦具有显著的防护作用。表明该药可保护肝细胞免受脂质过氧化损伤。     

Melatonin-selenium nanoparticles inhibit oxidative stress and protect against hepatic injury induced by Bacillus Calmette-Guérin/lipopolysaccharide in mice

Melatonin-selenium nanoparticles (MT-Se), a novel complex, were synthesized by preparing selenium nanoparticles in melatonin medium. The present investigation was designed to determine the protective effects of MT-Se against Bacillus Calmette-Guérin (BCG)/lipopolysaccharide (LPS)-induced hepatic injury in mice. In BCG/LPS-induced hepatic injury model, MT-Se administered (i.g.) at doses of 5, 10, or 20 mg/kg to BCG/LPS-treated mice for 10 days, significantly reduced the increase in plasma aminotransferase, reduced the severe extent of hepatic cell damage and the immigration of inflammatory cells. The MT-Se particles also attenuated the increase in the content of thiobarbituric acid-reactive substances and enhanced the decrease in reduced activities of superoxide dismutase and glutathione peroxidase (GPx). However, treatment with MT-Se suppressed the increase in nitric oxide levels both in plasma and liver tissue. Furthermore, supplementation with MT-Se at the dose of 10 mg/kg (composed of 9.9 mg/kg melatonin and 0.1 mg/kg selenium) had great capability to protect against hepatocellular damage than a similar dose of melatonin (10 mg/kg) or selenium (0.1 mg/kg) alone. This effect may relate to its higher antioxidant efficacy in decreasing lipid peroxidation and increasing GPx activity. These results suggest that the mode of MT-Se hepatic protective action is, at least in part, related to its antioxidant properties.     

Protective effect of chitosan treatment against acetaminophen-induced hepatotoxicity

Acetaminophen (APAP) is the most commonly reported toxic ingestion in the world. Severe liver injury resulting from overdose or chronic use of APAP remains a significant clinical problem. In recent years, the mechanisms underlying liver injury caused by APAP have become much better understood. We have studied the protective effect of chitosan supplementation against APAP-induced hepatotoxicity with respect to changes in the levels of total and lipid-bound sialic acid in the serum and in the liver tissue and changes in the activity of diagnostic marker enzymes, lipid peroxidation, and ceruloplasmin oxidase enzyme in normal and experimental groups of rats. During the experimental period, chitosan (200 mg/kg body weight per day) was administered to APAP + chitosan-treated rats by oral gavage. Results showed that treatment with APAP induced a significant increase in the serum alanine aminotransferase and alkaline phosphatase activities, in total and lipid-bound sialic acids levels, and in the liver lipid peroxide content. The administration of chitosan significantly prevented APAP-induced alterations in the levels of diagnostic marker enzymes, total sialic acid, lipid-bound sialic acid, and malondialdehyde in the experimental groups of rats. Furthermore, chitosan administration increased the activity of ceruloplasmin oxidase. In conclusion, our results suggest that chitosan has a protective effect on APAP-induced hepatic injury in rats. The study sheds light on the therapeutic potential of chitosan in an APAP-induced hepatotoxicity model.     

Ethanol binging enhances hepatic microvascular responses to acetaminophen in mice

OBJECTIVE: Chronic alcoholism has been considered to be a risk for acetaminophen (APAP) hepatotoxicity, but little is known about the effect of binge alcohol drinking on APAP-induced liver injury. The present study was conducted to examine the effect of ethanol binging on APAP-induced hepatic microcirculatory dysfunction. METHODS: Male C57Bl/6 mice received 3 weekly ethanol binges (4 g/kg every 12 h x 5 doses/ week) or water binges. At 12 h after the last gavage, APAP (300 mg/kg) was given by oral gavage. In one group of mice, gadolinium chloride (GdCl3, 10 mg/kg) was intraperitoneally administered 2 and 1 days before the start of each weekly ethanol binge. RESULTS: Ethanol binging enhanced APAP-induced liver injury as indicated by ALT levels. Intravital microscopic study showed that APAP further increased the area occupied by infiltrated erythrocytes into the extrasinusoidal space as well as Kupffer cell phagocytic activity in ethanol-binged mice when compared with water-binged mice, while no significant differences in sinusoidal perfusion and leukocyte adhesion were observed. ALT levels after APAP were exacerbated in ethanol-binged mice treated with GdCl3, but APAP-induced hepatic microcirculatory dysfunction was not changed significantly. CONCLUSIONS: These results suggest that ethanol binging increases APAP-induced liver injury by exacerbating infiltration of the Disse space with blood cells. Kupffer cells exert a protective role in the liver against APAP intoxication following ethanol binging.     

Piperine,an active ingredient of black pepper attenuates acetaminophen–induced hepatotoxicity in mice

ObjectiveTo explore the hepatoprotective and antioxidant effects of piperine against acetaminophen-induced hepatotoxicity in mice.MethodsIn mice, hepatotoxicity was induced by a single dose of acetaminophen (900 mg/kg b.w. i.p.). Piperine (25 mg/kg b.w. i.p.) and standard drug silymarin (25 mg/kg b.w. i.p.) were given to mice, 30 min after the single injection of acetaminophen. After 4 h, the mice were decapitated. Activities of liver marker enzymes [(aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP)] and inflammatory mediator tumour necrosis factor-alpha (TNF-α) were estimated in serum, while lipid peroxidation and antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-s-transferase and glutathione) were determined in liver homogenate of control and experimental mice.ResultsAcetaminophen induction (900 mg/kg b.w. i.p.) significantly increased the levels of liver marker enzymes, TNF-α, and lipid peroxidation, and caused the depletion of antioxidant status. Piperine and silymarin treatment to acetaminophen challenged mice resulted in decreased liver marker enzymes activity, TNF-α and lipid peroxidation levels with increase in antioxidant status.ConclusionsThe results clearly demonstrate that piperine shows promising hepatoprotective effect as comparable to standard drug silymarin.     

Protective effects of chitosan oligosaccharide and its derivatives against carbon tetrachloride-induced liver damage in mice.

The protective effects of chitosan oligosaccharide (COS), d-glucosamine (GlcNH(2)) and N-acetyl-d-glucosamine (GlcNAc) on carbon tetrachloride (CCl(4))-induced hepatotoxicity and the possible mechanisms that involved were investigated in male ICR mice. CCl(4) (20mg/kg body weight, i.p.) administration induced marked increase in serum AST and ALT activities, primed liver lipid peroxidation, depleted sulfhydryl content, impaired total antioxidant capabilities and induced genotoxicity 24h after administration. Pretreatment with COS, GlcNH(2), and GlcNAc (1.5g/kg body weight, i.g.) for 12 consecutive days prior to CCl(4) challenge significantly induced metallothionein (MT) expression. Thus, the antioxidant defensive system in the body was strengthened to counteract the oxidative damage induced by the succedent CCl(4) administration. Serum AST and ALT activities were effectively decreased. Hepatic malondialdehyde formation was inhibited and sulfhydryl contents, total antioxidant capabilities were markedly restored. Genotoxicity as reflected by DNA fragmentation, however, was not mitigated by pretreatment with COS, GlcNH(2), and GlcNAc. Histophathologic results of liver also confirmed their hepato-protective effects. Pretreatment with COS, GlcNH(2), and GlcNAc also could significantly decrease serum creatinine and uric acid levels and inhibit lipid peroxidation in kidney homogenate. Our results suggest that pretreatment with COS, GlcNH(2), and GlcNAc can efficiently protect mice against CCl(4)-induced toxicity.     

Prevention of postischaemic lipid peroxidation and liver cell injury by iron chelation.

Liver ischaemia was induced by cross clamping the hilar pedicle for 30 minutes in groups of rats with or without treatment with the iron chelating agent desferrioxamine (deferoxamine, DFR). The groups included eight animals each and were divided into the following treatment categories: control; ischaemia alone; ischaemia with subsequent reperfusion; ischaemia preceded by DFR, 60 mg/kg body weight; and reperfusion preceded by 20, 40, or 60 mg/kg DFR. The drug was given intravenously five minutes before either ischaemia or reperfusion. Malondialdehyde (MDA), a product of lipid peroxidation, and histopathological changes of liver tissue samples were used as indicators of hepatocellular injury. Lipid peroxidation (MDA concentration in mumol/kg liver tissue) was highest (4.76 (1.19] after ischaemia without reperfusion and less pronounced (2.87 (0.34] after reperfusion. Both concentrations, however, were significantly (p less than 0.05) higher than basal (control) values (1.78 (0.27]. At 60 mg/kg body weight, DFR treatment reduced MDA to basal or even lower concentrations in both situations (1.98 (0.08) and 1.26 (0.06), respectively) with a corresponding improvement in liver histopathology. Lower DFR doses were less protective. The data suggest that liver ischaemia is associated with free radical initiated, and apparently iron catalysed lipid peroxidation, which can be significantly decreased by iron chelation.     

硫辛酰胺对db/db小鼠肝损伤的保护作用研究

目的观察硫辛酰胺(ALM)对db/db小鼠肝损伤的保护作用及可能机制。方法db/db小鼠随机分为糖尿病组(DM)和ALM组,C57BL/6J小鼠为正常对照组(NC),每组各6只。ALM组于第9周时予ALM[100 mg/(kg·d)]进行灌胃干预,干预8周后处死小鼠,检测生化指标及肝组织谷丙转氨酶(ALT)、谷草转氨酶(AST)、过氧化氢酶(CAT)活性及丙二醇(MDA)表达量,油红O、HE染色观察肝脏病理学改变,Western blot法检测肝组织中核因子E2相关因子2(Nrf2)、血红素氧合酶1(HO-1)蛋白水平。结果与NC组比较,DM组体重、TG、TC、FBG升高,MDA含量升高[(0.73±0.04)vs(0.92±0.17)nmol/mg,P<0.05],CAT活性降低[(1.08±0.18)vs(0.52±0.14)U/mg,P<0.05],ALT、AST活性升高[(16.85±3.84)vs(22.42±4.56)U/g,(6.07±1.91)vs(8.19±1.51)U/g,P<0.05],Nrf2、HO-1的表达升高[(0.33±0.25)vs(1.81±0.34),(0.29±0.13)vs(1.25±0.19),P<0.05]。与DM组比较,ALM组体重、TG、TC降低,MDA降低[(0.92±0.17)vs(0.56±0.11)nmol/mg,P<0.05],CAT活性升高[(0.52±0.14)vs(0.91±0.20)U/mg,P<0.05],ALT、AST活性降低[(22.42±4.56)vs(17.08±5.08)U/g,(8.19±1.51)vs(5.10±0.46)U/g,P<0.05],Nrf2、HO-1表达降低[(1.81±0.34)vs(1.01±0.30),(1.25±0.19)vs(0.52±0.17),P<0.05]。结论ALM可抑制T2DM小鼠肝损伤的发生发展,其机制可能是通过改善肝组织脂质沉积、抑制氧化应激,调节Nrf2、HO-1蛋白表达以实现。     

Acetaminophen overdose-induced liver injury in mice is mediated by peroxynitrite independently of the cyclophilin D-regulated permeability transition

Acetaminophen (APAP) is safe at therapeutic dosage but can cause severe hepatotoxicity if used at overdose. The mechanisms of injury are not yet fully understood, but previous reports had suggested that the mitochondrial permeability transition (mPT) may be involved in triggering hepatocellular necrosis. We aimed at inhibiting mitochondrial cyclophilin D (CypD), a key regulator of the mPT, as a potential therapeutic target in APAP hepatotoxicity. Wildtype mice treated with a high dose of APAP (600 mg/kg, intraperitoneal) developed typical centrilobular necrosis, which could not, however, be prevented by cotreatment with the selective CypD inhibitor, Debio 025 (alisporivir, DEB025, a nonimmunosuppressive cyclosporin A analog). Similarly, genetic ablation of mitochondrial CypD in Ppif-null mice did not afford protection from APAP hepatotoxicity. To determine whether APAP-induced peroxynitrite stress might directly activate mitochondrial permeabilization, independently of the CypD-regulated mPT, we coadministered the peroxynitrite decomposition catalyst Fe-TMPyP (10 mg/kg, intraperitoneal, 90 minutes prior to APAP) to CypD-deficient mice. Liver injury was greatly attenuated by Fe-TMPyP pretreatment, and mitochondrial 3-nitrotyrosine adduct levels (peroxynitrite marker) were decreased. Acetaminophen treatment increased both the cytosolic and mitochondria-associated P-JNK levels, but the c-jun-N-terminal kinase (JNK) signaling inhibitor SP600125 was hepatoprotective in wildtype mice only, indicating that the JNK pathway may not be critically involved in the absence of CypD. Conclusion: These data support the concept that an overdose of APAP results in liver injury that is refractory to pharmacological inhibition or genetic depletion of CypD and that peroxynitrite-mediated cell injury predominates in the absence of CypD.     

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.