辛伐他汀对高脂血症性脂肪肝治疗的实验研究

目的　探讨调脂药辛伐他汀对高脂血症性脂肪肝的作用。方法　通过高脂食饵饲养制备大鼠高脂血症性脂肪肝模型 ,分别检测模型组 (n =10 )和对照组 (n =10 )的肝指数 (肝重 /体重 )、肝功能、血脂、肝脂、血清、肝组织丙二醛 (MDA)含量及肝组织学改变。模型组剩余 2 0只大鼠随机分为两组 ,治疗组给予辛伐他汀 4mg/kg灌胃 ,每日 1次 ,4周后检测上述指标 ,并与未治疗组比较分析。 结果　高脂血症性脂肪肝模型肝指数、血脂、肝脂、血清及肝组织MDA含量显著升高 (P均 <0 .0 1) ,血脂与血清MDA含量呈正相关 (P <0 .0 1)。肝组织学呈轻、中度脂肪变 ,以小泡性脂滴为主 ;辛伐他汀治疗组血脂、肝脂、血清MDA含量显著降低 (P均 <0 .0 1) ,肝组织MDA含量降低 (P <0 .0 5 ) ,肝组织学接近正常。未治疗组肝脂有所降低 ,肝组织学有改善 ,但血脂增高持续存在。结论　辛伐他汀可安全、有效地用于高脂血症性脂肪肝的治疗。     

非诺贝特治疗酒精性与药物性脂肪肝的实验研究

目的 研究非诺贝特对酒精性脂肪肝以及药物性脂肪肝的作用,并探讨两种脂肪肝的发病机制。方法 建立酒精性脂肪肝和药物性脂肪肝大鼠模型并分为治疗组(80 mg/kg)和对照组。4周后处死,分别测定肝功能,血清甘油三酯(TG)、胆固醇(TC)、高密度脂酯(HDL),血清及肝组织丙二醛(MDA)、肝脂酯(HL),脂蛋白脂酶(LPL)及肝脏病理变化。 结果 酒精性脂肪肝非诺贝特组与对照组比较,血清TG治疗组为(1.07±0.06)mmol/L,对照组为(1.56±0.29)mmol/L,血清MDA分别为(1.10±0.22)nmol/L和(1.26±0.21)nmol/L,肝组织内MDA分别为(5.92±1.24)nmol/g和(7.42±1.22)nmol/g,血清内HL分别为(0.053±0.006)μEq·ml-1·h-1和(0.037±0.006)μEq·ml-1·h-1,LPL水平明显升高分别为(0.018±0.004)μEq·ml-1·h-1和(0.014±0.004)μEq·ml-1·h-1;肝组织HL分别为(0.075±0.010)μEq·ml-1·h-1和(0.065±0.007)μEq·ml-1·h-1,LPL分别为(0.022±0.014)μEq·ml-1·h-1和(0.008±0.002)μEq·ml-1·h-1,TC的水平无明显变化,肝内脂质含量分别为(26.01±1.69)mg/g和(71.45±2.66)mg/g,同时肝脏病理明显改善。药物性脂肪肝非诺贝特组与对照组比较肝脏病理改变差异无显著意义。 结论 非诺贝特治疗酒精性脂肪肝可以明显减少肝内脂质的含量,改     

非诺贝特治疗脂肪肝肝功能异常者高甘油三酯血症的安全性

目的:探讨非诺贝特在肝功能异常的脂肪肝患者治疗高甘油三酯血症的安全性。方法:应用非诺贝特0.1,3次/d,治疗57例经血生化检测和B超检查明确的肝功能异常之脂肪肝患者共4周,观察其服药前、后之肝功能及血脂水平的变化。结果:57例患者中有2例服药后发现肝功能恶化而停服非诺贝特,停服后肝功能未进一步恶化;另有5例出现消化道不良反应但无肝功能恶化,故坚持服药至4周。55例服药前TG、ALT、AST分别为3.57±1.25mmol/L、131.48±49.51 IU/L、85.16±22.23 IU/L,服药后分别为l.58±0.47mmol/L、46.09±20.18 IU/L、40.31±14.05 IU/L,服药前、后存在极显著差异(P<0.01、P<0.001. P<0.001)。结论;在严密监测肝功能的基础上.非诺贝特可安全地用于治疗肝功能异常之脂肪肝患者。     

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.     

不同治疗方案对乙硫氨酸所致小鼠脂肪肝模型的影响

目的：观察保肝药益肝灵与降脂药非诺贝特对乙硫氨酸致小鼠脂肪肝模型血脂、肝脂和肝功能的影响。方法：采用乙硫氨酸诱导小鼠脂肪肝模型，分男4给予保肝药物和降脂药物，检测血清和肝脏甘油三酯等指标，观察不同防治方隶的疗效。结果：在肝脂升高、肝功能异常的情况下，给予保肝药物益肝灵能显著降低肝脏甘油三酯的堆积，显著改善肝功能状况，给予降脂药非诺贝特能增加肝脏甘油三酯的堆积，与保肝组相比，肝脂的差异具有显著性意义。结论：在血脂正常而肝脂、肝功能异常时，应采取以保肝药物为主的改善肝功能的治疗措施。     

健肝消脂合剂对脂肪肝大鼠过氧化物的影响及肝脏病理学改变

[目的]进一步探讨健肝消脂合剂对高脂血症性脂肪肝大鼠肝脏脂变的改善及作用机制。[方法]采用高脂饮食建立营养性脂肪肝大鼠模型,设健肝消脂合剂大、小剂量治疗组和大、小剂量预防组,以东宝肝泰组（简称东宝组）、模型组、正常组为对照组,观察健肝消脂合剂对高脂血症性脂肪肝大鼠血清超氧化物歧化酶（SOD）、丙二醛（MDA）的影响及肝脏病理学的改变。[结果]模型组较正常血清MDA组显著升高,SOD显著降低（P〈0.01）;治疗组、预防组较模型组血清MDA显著降低,SOD升高（均P〈0.01）;模型组大鼠肝脏受损面积明显高于正常组（P〈0.01）;大、小剂量预防组和治疗组均明显低于模型组（P〈0.01）。[结论]健肝消脂合剂能有效地抑制肝细胞内氧应激-脂质过氧化损伤,显著改善脂肪肝病理变化;其作用机制可能通过减少脂质在肝脏沉积与减轻过氧化损伤改善脂肪肝。     

肝脂复煎剂对实验性脂肪肝的治疗效应

[目的]探讨肝脂复煎剂对实验性脂肪肝的治疗作用.[方法]通过高脂饮食饲养制备大鼠脂肪肝模型;肝脏病理切片证实造模成功.造模大鼠40只随机分为5组,肝脂复低、中、高剂量治疗组,饮食治疗组及模型对照组.分别检测各组大鼠的肝指数(肝重/体重)、肝功能、血脂、血糖、肝脂、血清和肝组织中丙二醛(MDA)及肝组织学改变.[结果]肝脂复煎剂组血脂改善、肝脂显著降低(P＜0.05,＜0.01),血清和肝组织中丙二醛(MDA)显著降低(P＜0.05,＜0.01),肝组织学接近正常.饮食治疗组改善不大.[结论]肝脂复煎剂可有效地用于实验性脂肪肝的治疗.     

辛伐他汀与非诺贝特对高血压伴高脂血症患者胰岛素抵抗的影响

目的　观察国产辛伐他汀 (京必舒新 )与非诺贝特对高血压伴高血脂患者胰岛素抵抗的影响。方法　将 13 1例高血压伴胰岛素抵抗及高血脂患者随机分成 2组。辛伐他汀组 65例 (男性 45例 ,女性 2 0例 ;平均年龄 5 0± 8.3岁 ) ,给辛伐他汀 2 0mg ,po ,qd。非诺贝特组 66例 (男性 47例 ,女性 19例 ;平均年龄 49± 7.6岁 ) ,给非诺贝特 10 0mg ,po ,Tid。两组疗程 12W。结果　 (1)辛伐他汀降低TC ,LDL -C明显优于非诺贝特 ;(2 )非诺贝特降低TG优于辛伐他汀 ;(3 )辛伐他汀治疗后空腹胰岛素明显下降 ,ISI明显增加 ,与非诺贝特组比较差异显著 (P <0 .0 0 1)。结论　辛伐他汀可显著改善高血压伴高血脂患者胰岛素抵抗     

消脂护肝方对非酒精性脂肪肝大鼠脂质过氧化的影响

目的:探讨中药"消脂护肝方"对非酒精性脂肪肝(NAEL)大鼠脂质过氧化(LP)的影响.方法:用CCl4和高脂饮食复合方法建立大鼠NAFL模型,造模期间给予中药"消脂护肝方"和西药"东宝肝泰"干预,6周后检测肝功能、血脂并观察肝组织病理变化,检测肝组织脂质含量和超氧化物歧化酶(SOD)、谷胱甘肽过氧化酶(GSH-PX)及丙二醛(MDA)的含量.结果:中药组和西药组肝组织病理改变较模型组明显减轻,肝组织脂质含量及MDA含量较模型组明显降低,SOD、GSH-PX含量则明显升高.结论:①消脂护肝方具有保护肝功能、降低血脂、抗肝脏脂质沉积的作用;②消脂护肝方具有减轻大鼠NAFL模型肝组织细胞LP反应的作用,对LP导致肝脏脂肪变性具有抑制作用.     

丹参注射液对非酒精性脂肪肝大鼠脂质代谢和TNF-α水平的影响

目的探讨丹参注射液对脂肪肝大鼠脂质代谢和TNF-α水平的影响。方法用高脂饲料建立大鼠非酒精性脂肪肝模型,并用丹参注射液进行干预治疗,观察药物对脂肪肝大鼠血脂水平、脂质过氧化水平、TNF-α水平及病理变化的影响。结果模型组大鼠血清和肝组织中均MDA水平升高,血清中SOD水平下降,丹参注射液降低血清中MDA水平;模型组TNF-α水平下降;模型组大鼠肝脂肪细胞沉着面积最大,并有一定程度的肝纤维组织增生。结论丹参注射液具有降血脂、改善脂质过氧化及抗脂肪沉着作用。     

血脂康对脂肪肝大鼠过氧化物酶体增殖物活化受体γ及小凹蛋白1的影响

目的探讨血脂康对高脂血症大鼠脂肪肝形成的影响及其可能机制。方法选择16只大鼠给予高脂饲养6周后,随机分为模型组8只大鼠饲以高脂饮食,血脂康组8只大鼠在饲以高脂饮食基础上给予血脂康300mg/kg·d);另选8只大鼠作为对照组,给予普通饮食。12周末,观察大鼠肝脏病理形态学变化,检测血脂、肝脏氧化应激水平,western blot法检测肝脏过氧化物酶体增殖物活化受体γ(PPARγ)及小凹蛋白1的表达。结果与对照组比较,模型组大鼠TC、LDL-C水平明显升高(P<0.01);肝细胞脂肪变性明显;肝脏超氧化物歧化酶活性明显下降、丙二醛含量明显增高(P<0.05);PPARγ蛋白表达明显下降、小凹蛋白1表达明显升高(P<0.05)。与模型组比较,血脂康组大鼠TC、LDL-C、TG水平明显下降(P<0.05);肝脂肪变性程度及氧化应激水平明显改善;PPARγ蛋白表达水平升高、小凹蛋白1表达明显下降(P<0.05)。结论血脂康能减轻高脂血症大鼠肝脏脂肪变性,可能与其在调脂同时上调PPARγ的表达,下调小凹蛋白1的表达,减少脂质进入肝细胞,从而减少肝脏氧化应激水平。     

Bezafibrate对大鼠高脂血症和脂肪肝形成的影响

目的探讨以降低甘油三酯为主的血脂调整药对高脂血症脂肪肝的防治作用。方法观察Ｂｅｚａｆｉｂｒａｔｅ对高脂饮食诱发Ｗｉｓｔａｒ大鼠高脂血症和脂肪肝形成的影响（治疗组,ｎ＝８）,并设模型组和正常饮食组作对照。结果与正常组相比,模型组血脂和肝匀浆脂肪含量均显著升高,肝组织学呈中至重度脂肪变。与模型组相比,治疗组血清甘油三酯和总胆固醇显著下降,但血清转氨酶和肝匀浆脂质含量却呈升高趋势,肝脏病理学变化与模型组基本相近。结论Ｂｅｚａｆｉｂｒａｔｅ虽可显著降低高脂饮食诱发的高脂血症,但对肝内脂肪沉积并无防治作用。     

Effect of insulin-sensitizing agents in combination with ezetimibe, and valsartan in rats with non-alcoholic fatty liver disease

AIM: To assess whether treatment with insulin-sensitizing agents (ISAs) in combination with ezetimibe and valsartan have greater effect on hepatic fat content and lipid peroxidation compared to monotherapy in the methionine choline-deficient diet (MCDD) rat model of non-alcoholic fatty liver disease (NAFLD). METHODS: Rats (n = 6 per group) were treated with different drugs, including MCDD only, MCDD diet with either metformin (200 mg/kg), rosiglitazone (3 mg/kg), metformin plus rosiglitazone (M R), ezetimibe (2 mg/ kg), valsartan (2 mg/kg), or combination of all drugs for a total of 15 wk. Liver histology, lipids, parameters of oxidative stress and TNF-alpha were measured. RESULTS: Fatty liver (FL) rats demonstrated severe hepatic fatty infiltration (> 91% fat), with an increase in hepatic TG ( 1263%, P < 0.001), hepatic cholesterol ( 245%, P < 0.03), hepatic MDA levels ( 225%, P < 0.001), serum TNF-alpha (17.8±10 vs 7.8±0.0, P < 0.001), but a decrease in hepatic alpha tocopherol (-74%, P < 0.001) as compared to the control rats. Combination therapy with all drugs produced a significant decrease in liver steatosis (-54%), hepatic TG (-64%), hepatic cholesterol (-31%) and hepatic MDA (-70%), but increased hepatic alpha tocopherol ( 443%) as compared to FL rats. Combination therapy with ISA alone produced a smaller decrease in liver steatosis (-32% vs -54%, P < 0.001) and in hepatic MDA levels (-55% vs -70%, P < 0.01), but a similar decrease in hepatic lipids when compared with the all drugs combination. TNF-alpha levels decreased significantly in all treatment groups except in ISA group. CONCLUSION: Combination therapies have a greater effect on liver fat content as compared to monotherapy. Rosiglitazone appears to improve hepatic steatosis to a greater extent than metformin.     

Effects of emodin on treating murine nonalcoholic fatty liver induced by high caloric laboratory chaw

AIM: To investigate the effects of emodin on the treatment of non-alcoholic fatty liver in rats induced by high caloric laboratory chaw. METHODS: Non-alcoholic fatty liver model was successfully established by feeding with high caloric laboratory chaw for 12 wk. Then the model rats were randomly divided into 3 groups, namely model control group, emodin group and dietary treatment group. The rats in emodin group were given emodin at dose of 40 mg/(kg·d) while animals in other groups were given distilled water of the same volume. The rats in model control group were fed with high caloric laboratory chaw while animals in other groups were fed with normal diet. Four weeks later, liver index (liver/body weight ratio), serum activities of liver-associated enzymes, blood lipid, fasting blood glucose, fasting plasma insulin, HOMA insulin resistance index (HOMA-IR), hepatic triglyceride content and histology features of all groups were assayed. The expression of hepatic peroxisomal proliferator activated receptor (PPAR) gamma was determined by RT-PCR. RESULTS: The body weight, liver index, serum activities of alanine aminotransferase (ALT), blood lipid, hepatic triglyceride content of model control group were significantly elevated, with moderate to severe hepatocyte steatosis. The expression of hepatic PPAR gamma mRNA was obviously reduced in model control group. Compared with model control group, the body weight, liver index, serum activities of ALT, blood lipids and hepatic triglyceride of emodin group significantly decreased and hepatic histology display was also greatly improved. Meanwhile, the expression of hepatic PPAR gamma mRNA was elevated. However, high serum activities of ALT and hyperlipidemia were persisted in dietary treatment group although liver index was decreased and liver histology was somewhat improved. CONCLUSION: It is suggested that emodin might be effective in the treatment of non-alcoholic fatty liver in rats. Its therapeutic mechanism could be associated with increasing the expression of hepatic PPAR gamma mRNA.     

Experimental study of osthole on treatment of hyperlipidemic and alcoholic fatty liver in animals

AIM: To evaluate the effects of osthole on fatty liver, and investigate the possible mechanism. METHODS: A quail model with hyperlipidemic fatty liver and rat model with alcoholic fatty liver were set up by feeding high fat diet and alcohol, respectively. These experimental animals were then treated with osthole 5-20 mg/kg for 6 wk, respectively. Whereafter, the lipid in serum and hepatic tissue, and coefficient of hepatic weight were measured. RESULTS: After treatment with osthole the levels of serum total cholesterol (TC), triglyceride (TG), lower density lipoprotein-cholesterol (LDL-C), coefficient of hepatic weight, and the hepatic tissue contents of TC and TG were significantly decreased. The activity of superoxide dismutase (SOD) in liver was improved. In alcohol-induced fatty liver rats, the level of malondialdehyde (MDA) in liver was decreased. In high fat-induced fatty liver quails, glutathione peroxidase (GSH-PX) in liver was significantly improved. The histological evaluation of liver specimens demonstrated that the osthole dramatically decreased lipid accumulation. CONCLUSION: These results suggested that osthole had therapeutic effects on both alcohol and high fat-induced fatty liver. The mechanism might be associated with its antioxidation.     

Changes in lipid metabolism in chronic hepatitis C

AIM: To investigate the relationship between certain biochemical parameters of lipid metabolism in the serum and steatosis in the liver. METHODS: The grade of steatosis (0-3) and histological activity index (HAI, 0-18) in liver biopsy specimens were correlated with serum alanine aminotransferase (ALT), total cholesterol and triglyceride levels in 142 patients with chronic hepatitis C (CH-C), and 28 patients with non-alcoholic fatty liver disease (NAFLD) without hepatitis C virus (HCV) infection. The serum parameters were further correlated with 1 797 age and sex matched control patients without any liver diseases. RESULTS: Steatosis was detected in 90 out of 142 specimens (63%) with CH-C. The ALT levels correlated with the grade of steatosis, both in patients with CH-C and NAFLD (P<0.01). Inserting the score values of steatosis as part of the HAI, correlation with the ALT level (P<0.00001) was found. The triglyceride and cholesterol levels were significantly lower in patients with CH-C (with and without steatosis), compared to the NAFLD group and to the virus-free control groups. CONCLUSION: Our study confirms the importance of liver steatosis in CH-C which correlates with lower lipid levels in the sera. Inclusion of the score of steatosis into HAI, in case of CH-C might reflect the alterations in the liver tissue more precisely, while correlating with the ALT enzyme elevation.     

Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, reduces hepatic steatosis and lipid peroxidation in fatty liver Shionogi mice with hereditary fatty liver.

BACKGROUND AND AIMS: The fatty liver Shionogi (FLS) mouse, a unique model for nonalcoholic fatty liver disease (NAFLD), is an inbred strain that develops spontaneous hepatic steatosis without obesity or diabetes mellitus. Peroxisome proliferator-activated receptor (PPAR) alpha controls fatty acid metabolism. In the present study, we investigated the effect of fenofibrate, a PPARalpha agonist, on hepatic steatosis in FLS mice. METHODS: Thirteen-week-old FLS mice were fed a diet with 0.1% fenofibrate (w/w) for 12 days. The degree of hepatic steatosis was estimated by histological examination and hepatic triglyceride levels. Expression levels of genes involved in fatty acid turnover, including Acox1, Cpt1a, Fabp1, Acadl, and Acadm, were determined by Northern blot analyses. We measured levels of lipid peroxidation, glutathione, and anti-oxidative enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, in the liver. RESULT: Treatment of FLS mice with fenofibrate improved hepatic steatosis by activating expression of genes involved in fatty acid turnover and decreased hepatic lipid peroxidation. Fenofibrate increased the activity of catalase by upregulating its mRNA levels. CONCLUSION: Fenofibrate, which is currently used in therapy of hyperlipidemia, might also be useful for treating patients with NAFLD even in cases where NAFLD is not associated with obesity or diabetes mellitus.     

Reduction of hepatosteatosis and lipid levels by an adipose differentiation-related protein antisense oligonucleotide

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive triglyceride accumulation in hepatocytes. Expression of the lipid droplet protein adipose differentiation-related protein (ADRP) is increased in NAFLD, but whether this is causally linked to hepatic lipid metabolism is unclear. We postulated that a reduction in ADRP would ameliorate hepatic steatosis and improve insulin action. METHODS: Leptin deficient Lep(ob/ob) and diet-induced obese (DIO) mice were treated with antisense oligonucleotide (ASO) against ADRP, and effects on hepatic and serum lipids and glucose homeostasis were examined. RESULTS: ADRP ASO specifically decreased ADRP mRNA and protein levels in the livers of Lep(ob/ob) and DIO mice, without altering the levels of other lipid droplet proteins, that is, S3-12 and TIP47. ADRP ASO suppressed expression of lipogenic genes, reduced liver triglyceride content without affecting cholesterol, attenuated triglyceride secretion, and decreased serum triglyceride and alanine aminotransaminase levels. The reduction in hepatic steatosis by ADRP ASO was associated with improvement in glucose homeostasis in both Lep(ob/ob) and DIO mice. CONCLUSIONS: This study demonstrates a crucial role for the lipid droplet protein ADRP in regulation of lipid metabolism. Reduction in hepatic ADRP level using an antisense oligonucleotide reverses hepatic steatosis, hypertriglyceridemia, and insulin resistance in obese mice, suggesting that ADRP may be targeted for the treatment of NAFLD and associated lipid and glucose abnormalities.