化痰祛湿活血方治疗非酒精性脂肪性肝炎的临床研究及作用机制探讨
|
摘要
非酒精性脂肪性肝病(NAFLD)发病率逐年增加,非酒精性脂肪性肝炎(NASH)是其向肝硬化、肝功能衰竭发展的重要环节,已成为目前肝病领域的新挑战。目前尚无专用于治疗NASH的药物,中医药在治疗NASH方面具有一定的优势,导师在多年临床研究基础上积累了丰富的经验,制定了化痰祛湿活血方有效方剂,经临床应用效果良好。为进一步明确其临床疗效和作用机制,开展本研究。
目的：探讨化痰祛湿活血方治疗NASH的临床疗效和作用机制,为临床治疗NASH提供依据。
方法：①临床研究：采用多中心、随机、阳性对照临床研究方法,从4个分中心共收集NASH患者202例,分为治疗组和对照组,两组在健康教育、饮食运动基础上,治疗组使用化痰祛湿活血方颗粒剂1剂/d；对照组使用多烯磷脂酰胆碱(易善复)胶囊,456mmg/次,3次/d；疗程3个月,随访3个月。观察治疗、随访后患者血清ALT、TG、 AST、TC、肝/脾CT值、症状体征、体重指数等的变化；评价化痰祛湿活血方治疗NASH患者的临床疗效。②实验研究：根据NASH的发病机理,选择与其相关的血清ALT、AST、TG、TC.肝匀浆游离脂肪酸(FFA),肝指数、肝脏病理组织学,肝组织细胞色素P4502E1(cytochrome P4502E1, CYP2E1)和过氧化物酶体增殖物激活受体α(peroxisome proliferator-activated receptor-a, PPARa)基因表达等作为观察指标。具体的实验过程是：取SD雄性大鼠72只,随机分为空白组、模型组、多烯磷脂酰胆碱胶囊组(对照组)和化痰祛湿活血方高(高剂量组)、中(中剂量组)、低(低剂量组)剂量组。使用高脂饲料联合腹腔注射四环素进行造模,第7周实验结束时处死全部实验动物,腹主动脉采血；之后迅速取出肝脏称肝湿重,留取肝脏标本。观察肝湿重、肝指数、病理组织学变化(光学显微镜、透射电镜),检测血清谷丙转氨酶(ALT)、谷草转氨酶(AST)、甘油三酯(TG)、总胆固醇(TC)、肝匀浆FFA含量、肝组织CYP2E1、PPARα基因表达情况(RT-PCR法检测)等指标。
结果：临床及实验研究结果分述如下：
1.临床研究：①治疗组与对照组在治疗前后降低血清ALT及TG水平均有显著性差别(P<0.05),说明两组在保肝降酶、降TG方面均具有明显的作用。两组间治疗后比较治疗组在降低ALT、TG方面优于对照组,差异有显著性意义(P<0.05)。两组在改善肝/脾CT值治疗前后比较有显著差异(P<0.05),两组间治疗后比较也有显著差异(P<0.05)。
②两组在减轻体重指数(BMI)方面,治疗组、对照组组内治疗前后比较有显著性差异(P<0.05),治疗后两组比较无显著性差异(P>0.05),说明治疗组、对照组均可有效减轻体重指数。治疗组、对照组组内治疗前后比较症状和体征积分有显著性差异(P<0.05)。治疗组治疗后在改善肢体困重、胁胀胁痛、脘腹胀满、食少纳呆、大便溏薄症状方面优于对照组,差异有显著性(P<0.05)。
2.实验研究结果显示：①各用药组与模型组比较：各用药组肝指数、血清ALT、AST、 TC、TG和肝匀浆FFA含量均有不同程度下降,以化痰祛湿活血方高、中剂量组疗效最优(P<0.01或P<0.05)。化痰祛湿活血方高、中、低剂量组及对照组肝组织CYP2E1基因表达水平均有显著降低(P<0.01)。化痰祛湿活血方高、中剂量组PPAR α基因表达水平显著升高(P<0.01)。
②化高、中剂量组与对照组相比：高剂量组、中剂量组的肝湿重、病理组织学改善明显；血清ALT、AST、TC、TG、肝匀浆FFA含量显著降低(P<0.05)；高剂量组、中剂量组抑制CYP2E1基因表达效果明显优于对照组(P<0.01或P<0.05)；化痰祛湿活血方高、中剂量组的PPAR α基因表达水平较对照组显著升高(P<0.05)化高、中剂量组与低剂量组相比有显著性差异(P<0.01或P<0.05)。化痰祛湿活血方高、中剂量组之间比较无显著性差异(P>0.05)。
③病理学观察：光学显微镜显示：化痰祛湿活血方高、中剂量组与模型组脂肪变性比较有非常显著性差异(P<0.01),高剂量组与对照组比较有显著性差异(P<0.05),高剂量组与中剂量组比较有显著性差异(P<0.05),高剂量组与低剂量组比较有非常显著性差异(P<0.01),中剂量组与低剂量组比较有显著性差异(P<0.05)。透射电镜显示：与模型组相比,对照组、高剂量组、中剂量组均可升高肝细胞线粒体体密度(Vv)、比膜面(δm)、粗面内质网比膜面(δm),有显著性差异(P<0.01),均可降低肝细胞内脂滴体密度(Vv)、线粒体比表面(δ),有显著性差异(P<0.01)。高剂量组优于中剂量组和对照组(P<0.01),中剂量组与对照组效果相当。
结论：①化痰祛湿活血方治疗非酒精性脂肪性肝炎痰湿瘀阻证患者在降低血清ALT、TG,提高肝／脾CT值,改善症状体征方面优于多烯磷脂酰胆碱胶囊,与多烯磷脂酰胆碱胶囊均有降低患者BMI作用。化痰祛湿活血方适用于非酒精性脂肪性肝炎(痰湿瘀阻证)的患者,尚未发现不良反应,是一种有效安全的方药。
②采用高脂饲料联合四环素腹腔注射,造模时间短,成功率高,是一种较为理想的大鼠NASH造模方法。化痰祛湿活血方各剂量组均可有效降低NASH模型大鼠的肝湿重、肝指数、血清ALT、AS、TC、TG及肝匀浆FFA水平,改善病理组织学变化,具有显著的抗脂肪肝作用；化痰祛湿活血方可激活PPAR α mRNA表达,纠正肝脏脂质代谢紊乱；同时可抑制CYP2E1mRNA表达,阻止脂质过氧化反应。化痰祛湿活血方在增强大鼠PPAR α的表达的同时又可抑制CYP2E1表达,故不会加重脂质过氧化作用对肝脏的损伤,而是最终发挥了降低血脂、保肝降酶、阻止或减轻脂肪肝形成的作用,这可能是化痰祛湿活血方防治NASH的重要作用机制之一。化痰祛湿活血方可显著改善肝脏脂肪沉积,其治疗NASH的机制可能是通过增加线粒体嵴和线粒体数量,改善粗面内质网脱颗粒现象,保护肝细胞线粒体和内质网,恢复其形态结构和功能,增强肝细胞的能量代谢,从而达到治疗NASH的作用。
With the morbidity of non-alcohol fatty liver disease increasing year by year, NASH is critical in the development of liver fibrosis and liver failure, which has became a new challenge in the field of liver diseases research. At present, there is still no specific medicine for NASH, but the Chinese traditional medicine has its advantage on NASH. With many years of clinic research and experience, a recipe of HTQF (hua tan qu shi huo xue fang) has been formulated by our tutor and that has a good effect. What's more, after years of clinical application, the effect is inspiring. To further clarify the clinical efficacy and therapeutic mechanism, this study is implemented.
Objective:to implore the clinical efficacy and therapeutic mechanism of HTQF. to provide the theoretic evidence for the clinic application of HTQF.
Methods:the study was divided into two parts.1. Clinical research:A multi-center randomized controlled clinical study was done on202NASH patients from four sub-centers which were divided into the treatment group and the control group. Base on the health education, diet and exercise, the treatment group was administrated HTQF one dose per day and the control group polyene phosphatidylcholine three times per day. The course of the study was three months and the follow-up was three months too. After that the ALT, AST, TC, FFA of the liver homogenate, the ratio of liver/spleen CT values, the signs and symptoms, Body Mass index were observed to evaluate the clinical efficacy of HTQF on NASH.2.experimental study:the ALT, AST, TG, TC, FFA of the liver homogenate, the liver histopathology, the liver cytochrome P4502E1, the PPARa-mRNA were detected as the observation targets according to the NASH pathogenesis.72male rats were divided into6groups randomly, the normal group, the model group, the polyene phosphatidylcholine group, the HTQF high, medium and low dose group. NASH rat model was duplicated with high fat diet and tetracycline intraperitoneal injection. The animals were sacrificed after7weeks. After the blood collected from the abdominal aorta, the liver wet weights were measured and the liver specimens kept. The liver index and the histopathological changes (light microscopy and electron microscopy) were observed. The ALT, AST, TC, FFA of the liver homogenate, the liver cytochrome P4502E1, the PPARa-mRNA and so on were investigated too.
Result:the results of the clinical research and experimental study are displaced as follow.
1. Clinical research
①The levels of serum ALT and TG, in treatment and control group, declined significantly after therapy (P<0.05), which indicated that the two groups were all effective in protecting liver function, reducing enzymes and decreasing TG, while the former groups were superior to the latter group (P<0.05). The ratio of liver/spleen CT values, in treatment and control group, were reduced significantly after therapy (P<0.05) and the former groups were superior to the latter group too (P<0.05)
②The BMI, in treatment and control group, declined significantly after therapy (P<0.05), but groups comparison showed no difference in statistics (P>0.05),which indicated that the two groups were all effective in decreasing BMI. Integration of signs and symptoms in treatment and control group declined significantly after therapy (P<0.05) and the former groups were more effective in ameliorating symptoms, such as heavy sensation in the limbs and body, hypochondriac distention and pain, abdominal fullness and distention, eating less, anorexia and loose stool (P<0.05)
2. Experimental study
①Treatment and model group comparison The content of liver index, serum ALT, AST, TC, TG and liver homogenate FFA, in treatment and control group, declined significantly at different level, after therapy (P<0.05), with the high-dose and medium-dose HTQF the most effective (P<0.01, P<0.05). The expression of CYP2E1-mRNA in hepatic tissue were all depressed in high-dose, medium-dose and low-dose HTQF and Polyene group (P<0.01), while the expression of PPARa-mRNA in hepatic tissue were elevated in high-dose and medium-dose HTQF group (P<0.01)
②High-dose, medium-dose HTQF and Polyene group comparison When compared with Polyene group, several indexs changed significantly, which included ameliorated liver wet weight and histopathology, decreased level of serum ALT, AST, TC, TG and liver homogenate FFA, depressed CYP2E1-mRNA and elevated PPARa-mRNA(P<0.05), with no significantly different among the two groups of HTQF (P>0.05)
③pathology The degree of steatosis, under light microscope, had significant difference between high-dose or medium-dose HTQF group and model group (P<0.01). There were significant differences when comparing either positive control (P<0.05), medium-dose HTQF group (P<0.05) or low-dose HTQF group (P<0.01) with high-dosed HTQSHXF group. There was significant difference between middle-dose and low-dose HTQF group too (P<0.05). Under electron microscope, there were significant difference of the elevated liver cells mitochondria bulk density (Vv), membrane density (δm) and rough endoplasmic reticulum membrane density (δm) when positive control group, high-dosed or middle-dosed HTQSHXF group compared with model group (P<0.05).There were significant difference of the decreased lipid drops bulk density (Vv) and mitochondrion specific surface (δ) too. While high-dose HTQF was superior to the medium-dose HTQF group and Polyene control group (P<0.01) with no significant difference between the latter two groups.
Conclusion:As regarding to reducing the ALT, TG of the serum, raising the ratio of liver/spleen CT values, improving the clinical symptoms, the HTQF group was superior to the polyene group on NASH of phlegm and stasis. HTQF and polyene both can relieve the BMI. By far there are no side effect of HTQF on NASH of phlegm and stasis and HTQF is a safe and effective recipe. Using high fat diet and tetracycline intraperitoneal injection to duplicate NASH rat model is an ideal method, which is time saving and has high success rate. By reducing the wet liver weight, decreasing the index of liver, lowering the ALT, AST, TC, TG of serum and the FFA of liver homogenate, and improving the liver histopathology, HTQF has the good effect of anti-fatty liver. HTQF can induce the expression of PPARa-mRNA and correct the lipid metabolism disorders. At the same time HTQF can suppress the expression of CYP2E2-mRNA to prevent the lipid peroxidation. By protecting liver damage through preventing lipid peroxidation, HTQF can lower blood lipids, protect liver function and reduce the lever of liver transminases, so as to resist the formation of fatty liver, which may be one of its mechanism on NASH. HTQF can reduce the liver fat deposition. By increasing the mitochondria cristae and its number, improving the degranulation of rough endoplasmic reticulum, protecting the mitochondria and endoplasmic reticulum, restoring its morphology and function, enhancing the energy metabolism of the liver cells, HTQF owns the curative effect on NASH.
目的：探讨化痰祛湿活血方治疗NASH的临床疗效和作用机制,为临床治疗NASH提供依据。
方法：①临床研究：采用多中心、随机、阳性对照临床研究方法,从4个分中心共收集NASH患者202例,分为治疗组和对照组,两组在健康教育、饮食运动基础上,治疗组使用化痰祛湿活血方颗粒剂1剂/d；对照组使用多烯磷脂酰胆碱(易善复)胶囊,456mmg/次,3次/d；疗程3个月,随访3个月。观察治疗、随访后患者血清ALT、TG、 AST、TC、肝/脾CT值、症状体征、体重指数等的变化；评价化痰祛湿活血方治疗NASH患者的临床疗效。②实验研究：根据NASH的发病机理,选择与其相关的血清ALT、AST、TG、TC.肝匀浆游离脂肪酸(FFA),肝指数、肝脏病理组织学,肝组织细胞色素P4502E1(cytochrome P4502E1, CYP2E1)和过氧化物酶体增殖物激活受体α(peroxisome proliferator-activated receptor-a, PPARa)基因表达等作为观察指标。具体的实验过程是：取SD雄性大鼠72只,随机分为空白组、模型组、多烯磷脂酰胆碱胶囊组(对照组)和化痰祛湿活血方高(高剂量组)、中(中剂量组)、低(低剂量组)剂量组。使用高脂饲料联合腹腔注射四环素进行造模,第7周实验结束时处死全部实验动物,腹主动脉采血；之后迅速取出肝脏称肝湿重,留取肝脏标本。观察肝湿重、肝指数、病理组织学变化(光学显微镜、透射电镜),检测血清谷丙转氨酶(ALT)、谷草转氨酶(AST)、甘油三酯(TG)、总胆固醇(TC)、肝匀浆FFA含量、肝组织CYP2E1、PPARα基因表达情况(RT-PCR法检测)等指标。
结果：临床及实验研究结果分述如下：
1.临床研究：①治疗组与对照组在治疗前后降低血清ALT及TG水平均有显著性差别(P<0.05),说明两组在保肝降酶、降TG方面均具有明显的作用。两组间治疗后比较治疗组在降低ALT、TG方面优于对照组,差异有显著性意义(P<0.05)。两组在改善肝/脾CT值治疗前后比较有显著差异(P<0.05),两组间治疗后比较也有显著差异(P<0.05)。
②两组在减轻体重指数(BMI)方面,治疗组、对照组组内治疗前后比较有显著性差异(P<0.05),治疗后两组比较无显著性差异(P>0.05),说明治疗组、对照组均可有效减轻体重指数。治疗组、对照组组内治疗前后比较症状和体征积分有显著性差异(P<0.05)。治疗组治疗后在改善肢体困重、胁胀胁痛、脘腹胀满、食少纳呆、大便溏薄症状方面优于对照组,差异有显著性(P<0.05)。
2.实验研究结果显示：①各用药组与模型组比较：各用药组肝指数、血清ALT、AST、 TC、TG和肝匀浆FFA含量均有不同程度下降,以化痰祛湿活血方高、中剂量组疗效最优(P<0.01或P<0.05)。化痰祛湿活血方高、中、低剂量组及对照组肝组织CYP2E1基因表达水平均有显著降低(P<0.01)。化痰祛湿活血方高、中剂量组PPAR α基因表达水平显著升高(P<0.01)。
②化高、中剂量组与对照组相比：高剂量组、中剂量组的肝湿重、病理组织学改善明显；血清ALT、AST、TC、TG、肝匀浆FFA含量显著降低(P<0.05)；高剂量组、中剂量组抑制CYP2E1基因表达效果明显优于对照组(P<0.01或P<0.05)；化痰祛湿活血方高、中剂量组的PPAR α基因表达水平较对照组显著升高(P<0.05)化高、中剂量组与低剂量组相比有显著性差异(P<0.01或P<0.05)。化痰祛湿活血方高、中剂量组之间比较无显著性差异(P>0.05)。
③病理学观察：光学显微镜显示：化痰祛湿活血方高、中剂量组与模型组脂肪变性比较有非常显著性差异(P<0.01),高剂量组与对照组比较有显著性差异(P<0.05),高剂量组与中剂量组比较有显著性差异(P<0.05),高剂量组与低剂量组比较有非常显著性差异(P<0.01),中剂量组与低剂量组比较有显著性差异(P<0.05)。透射电镜显示：与模型组相比,对照组、高剂量组、中剂量组均可升高肝细胞线粒体体密度(Vv)、比膜面(δm)、粗面内质网比膜面(δm),有显著性差异(P<0.01),均可降低肝细胞内脂滴体密度(Vv)、线粒体比表面(δ),有显著性差异(P<0.01)。高剂量组优于中剂量组和对照组(P<0.01),中剂量组与对照组效果相当。
结论：①化痰祛湿活血方治疗非酒精性脂肪性肝炎痰湿瘀阻证患者在降低血清ALT、TG,提高肝／脾CT值,改善症状体征方面优于多烯磷脂酰胆碱胶囊,与多烯磷脂酰胆碱胶囊均有降低患者BMI作用。化痰祛湿活血方适用于非酒精性脂肪性肝炎(痰湿瘀阻证)的患者,尚未发现不良反应,是一种有效安全的方药。
②采用高脂饲料联合四环素腹腔注射,造模时间短,成功率高,是一种较为理想的大鼠NASH造模方法。化痰祛湿活血方各剂量组均可有效降低NASH模型大鼠的肝湿重、肝指数、血清ALT、AS、TC、TG及肝匀浆FFA水平,改善病理组织学变化,具有显著的抗脂肪肝作用；化痰祛湿活血方可激活PPAR α mRNA表达,纠正肝脏脂质代谢紊乱；同时可抑制CYP2E1mRNA表达,阻止脂质过氧化反应。化痰祛湿活血方在增强大鼠PPAR α的表达的同时又可抑制CYP2E1表达,故不会加重脂质过氧化作用对肝脏的损伤,而是最终发挥了降低血脂、保肝降酶、阻止或减轻脂肪肝形成的作用,这可能是化痰祛湿活血方防治NASH的重要作用机制之一。化痰祛湿活血方可显著改善肝脏脂肪沉积,其治疗NASH的机制可能是通过增加线粒体嵴和线粒体数量,改善粗面内质网脱颗粒现象,保护肝细胞线粒体和内质网,恢复其形态结构和功能,增强肝细胞的能量代谢,从而达到治疗NASH的作用。
With the morbidity of non-alcohol fatty liver disease increasing year by year, NASH is critical in the development of liver fibrosis and liver failure, which has became a new challenge in the field of liver diseases research. At present, there is still no specific medicine for NASH, but the Chinese traditional medicine has its advantage on NASH. With many years of clinic research and experience, a recipe of HTQF (hua tan qu shi huo xue fang) has been formulated by our tutor and that has a good effect. What's more, after years of clinical application, the effect is inspiring. To further clarify the clinical efficacy and therapeutic mechanism, this study is implemented.
Objective:to implore the clinical efficacy and therapeutic mechanism of HTQF. to provide the theoretic evidence for the clinic application of HTQF.
Methods:the study was divided into two parts.1. Clinical research:A multi-center randomized controlled clinical study was done on202NASH patients from four sub-centers which were divided into the treatment group and the control group. Base on the health education, diet and exercise, the treatment group was administrated HTQF one dose per day and the control group polyene phosphatidylcholine three times per day. The course of the study was three months and the follow-up was three months too. After that the ALT, AST, TC, FFA of the liver homogenate, the ratio of liver/spleen CT values, the signs and symptoms, Body Mass index were observed to evaluate the clinical efficacy of HTQF on NASH.2.experimental study:the ALT, AST, TG, TC, FFA of the liver homogenate, the liver histopathology, the liver cytochrome P4502E1, the PPARa-mRNA were detected as the observation targets according to the NASH pathogenesis.72male rats were divided into6groups randomly, the normal group, the model group, the polyene phosphatidylcholine group, the HTQF high, medium and low dose group. NASH rat model was duplicated with high fat diet and tetracycline intraperitoneal injection. The animals were sacrificed after7weeks. After the blood collected from the abdominal aorta, the liver wet weights were measured and the liver specimens kept. The liver index and the histopathological changes (light microscopy and electron microscopy) were observed. The ALT, AST, TC, FFA of the liver homogenate, the liver cytochrome P4502E1, the PPARa-mRNA and so on were investigated too.
Result:the results of the clinical research and experimental study are displaced as follow.
1. Clinical research
①The levels of serum ALT and TG, in treatment and control group, declined significantly after therapy (P<0.05), which indicated that the two groups were all effective in protecting liver function, reducing enzymes and decreasing TG, while the former groups were superior to the latter group (P<0.05). The ratio of liver/spleen CT values, in treatment and control group, were reduced significantly after therapy (P<0.05) and the former groups were superior to the latter group too (P<0.05)
②The BMI, in treatment and control group, declined significantly after therapy (P<0.05), but groups comparison showed no difference in statistics (P>0.05),which indicated that the two groups were all effective in decreasing BMI. Integration of signs and symptoms in treatment and control group declined significantly after therapy (P<0.05) and the former groups were more effective in ameliorating symptoms, such as heavy sensation in the limbs and body, hypochondriac distention and pain, abdominal fullness and distention, eating less, anorexia and loose stool (P<0.05)
2. Experimental study
①Treatment and model group comparison The content of liver index, serum ALT, AST, TC, TG and liver homogenate FFA, in treatment and control group, declined significantly at different level, after therapy (P<0.05), with the high-dose and medium-dose HTQF the most effective (P<0.01, P<0.05). The expression of CYP2E1-mRNA in hepatic tissue were all depressed in high-dose, medium-dose and low-dose HTQF and Polyene group (P<0.01), while the expression of PPARa-mRNA in hepatic tissue were elevated in high-dose and medium-dose HTQF group (P<0.01)
②High-dose, medium-dose HTQF and Polyene group comparison When compared with Polyene group, several indexs changed significantly, which included ameliorated liver wet weight and histopathology, decreased level of serum ALT, AST, TC, TG and liver homogenate FFA, depressed CYP2E1-mRNA and elevated PPARa-mRNA(P<0.05), with no significantly different among the two groups of HTQF (P>0.05)
③pathology The degree of steatosis, under light microscope, had significant difference between high-dose or medium-dose HTQF group and model group (P<0.01). There were significant differences when comparing either positive control (P<0.05), medium-dose HTQF group (P<0.05) or low-dose HTQF group (P<0.01) with high-dosed HTQSHXF group. There was significant difference between middle-dose and low-dose HTQF group too (P<0.05). Under electron microscope, there were significant difference of the elevated liver cells mitochondria bulk density (Vv), membrane density (δm) and rough endoplasmic reticulum membrane density (δm) when positive control group, high-dosed or middle-dosed HTQSHXF group compared with model group (P<0.05).There were significant difference of the decreased lipid drops bulk density (Vv) and mitochondrion specific surface (δ) too. While high-dose HTQF was superior to the medium-dose HTQF group and Polyene control group (P<0.01) with no significant difference between the latter two groups.
Conclusion:As regarding to reducing the ALT, TG of the serum, raising the ratio of liver/spleen CT values, improving the clinical symptoms, the HTQF group was superior to the polyene group on NASH of phlegm and stasis. HTQF and polyene both can relieve the BMI. By far there are no side effect of HTQF on NASH of phlegm and stasis and HTQF is a safe and effective recipe. Using high fat diet and tetracycline intraperitoneal injection to duplicate NASH rat model is an ideal method, which is time saving and has high success rate. By reducing the wet liver weight, decreasing the index of liver, lowering the ALT, AST, TC, TG of serum and the FFA of liver homogenate, and improving the liver histopathology, HTQF has the good effect of anti-fatty liver. HTQF can induce the expression of PPARa-mRNA and correct the lipid metabolism disorders. At the same time HTQF can suppress the expression of CYP2E2-mRNA to prevent the lipid peroxidation. By protecting liver damage through preventing lipid peroxidation, HTQF can lower blood lipids, protect liver function and reduce the lever of liver transminases, so as to resist the formation of fatty liver, which may be one of its mechanism on NASH. HTQF can reduce the liver fat deposition. By increasing the mitochondria cristae and its number, improving the degranulation of rough endoplasmic reticulum, protecting the mitochondria and endoplasmic reticulum, restoring its morphology and function, enhancing the energy metabolism of the liver cells, HTQF owns the curative effect on NASH.
引文
[1]中华医学会肝病学分会脂肪肝和酒精性肝病学组.非酒精性脂肪性肝病诊疗指南(2010年修订版)[J].中华肝脏病杂志.2010,18(3).163-166.
[2]Farrell GC, Larter CZ. Nonalcoholic fatty liver disease:from steatosis to cirrhosis.Hepatology,2006,43(2Suppl1):S99-S112.
[3]de Alwis NM. Day CP. Non-alcoholic fatty liver disease:the mist gradually clears. J Hepatol.2008,48 Suppl 1:S104-S112.
[4]Angulo P.GI epidemiology:nonalcoholic fatty liver disease [J].Aliment Pharmacol Ther,2007,25(8):883-889.
[5]Fan JG,Li F,Cai XB,et al.The importance of metabolic factors for the increasing prevalence of fatty liver in shanghai factory workers[J].J Gastroenterol Hepatol,2007,22(5):663-558.
[6]赵文霞,段荣章,刘君颖.1163例非酒精性脂肪肝患者与气虚质痰湿质相关性研究[J].辽宁中医杂志,2010,37(8)：1543-1544.
[7]张慧,胡义扬.肿瘤坏死因子α、脂联素与非酒精性脂肪性肝病[J].肝脏,2006,11(2)：137-139.
[8]曾民德.脂肪肝发病机制及其二次打击假设[J].中华消化杂志,2002,22(3)：167-168.
[9]杨建辉.林鹤和治脂肪肝的经验[J].江西中医药,2006,31(3)：1-2.
[10]王天明.赵国荣教授治疗脂肪肝经验[J].湖南中医杂志,2006,22(3)：42.
[11]周琪,刘鉴.李军教授从痰瘀论治脂肪肝临床经验探要[J].实用中医内科杂志,2008,22(1)：15-16.
[12]胡怀强,周永红,范玉芹.王新陆教授从浊论治脂肪肝经验撷著[J].中华中医药学刊,2007,25(9)：1781-1782.
[13]党中勤.十味肝脂康胶囊治疗脂肪肝62例[J].陕西中医,2003,24(7)：589.
[14]叶未设.中医对脂肪肝的认识及防治[J].中国热带医学,2004,4(6)：1023.
[15]韩加强,孟庆敏.脂肪肝的辨证论治[J].亚太传统医药,2007,3(2)：62.
[16]陈妹娴,应爱兰,辨证分型治疗脂肪肝探识[J].实用中医内科杂志,2006,20(4)：384.
[17]林艳,于敏,田谧,等.辨证治疗脂肪肝112例[J].中国中医急症,2007,16(8)： 1000-1001.
[18]陈腾云,何敏.脂肪肝中医辨证论治体会[J].中国误诊学杂志,2005,5(13)：2550-2551.
[19]李少东,李红山,冯琴,等.脂肪肝中医证型分类的文献分析[J].中西医结合肝病杂志,2006,16(4)：255-257.
[20]李玉权,杨钦河,谢维宁,等.疏肝健脾法治疗非酒精性脂肪肝35例[J].中医杂志,2007,48(9)：824-825.
[21]黄志平,林燕萍,张萍,等.茵陈越鞠汤治疗非酒精性脂肪性肝炎的临床观察[J].中华中医药学刊,2008,26,(5)：1100-1101.
[22]石拓,叶勇,时昭红,等.化痰活血方治疗高脂非酒精性脂肪肝患者50例[J].中国中西医结合消化杂志,2007,15(5)：344-345.
[23]谢立芳.“益气活血方”治疗非酒精性脂肪性肝病患者28例[J].江苏中医药,2010,42(4)：39.
[24]张卫星,吴忆东.补肝肾法治疗2型糖尿病性非酒精性脂肪肝50例[J].浙江中医杂志.2009,44(4).269.
[25]黄欣,张哲永.当飞利肝宁胶囊治疗非酒精性脂肪性肝病32例临床观察[J].中医杂志,2007,48(6)：524-525.
[26]程勇,赵亚敏,苏剑,等.水飞蓟宾胶囊对非酒精性脂肪性肝炎患者血清IL-18、IL-8、TNF-α、肝酶及血脂的影响[J].中国老年学杂志,2010,30(7)：979-980.
[27]赵文霞,张玉禄.消脂护肝胶囊对非酒精性脂肪肝患者胰岛素抵抗及瘦素水平的影响[J].中医研究,2005,18(5)：21-23.
[28]闫妍,徐亮,宓余强.壳脂胶囊治疗非酒精性脂肪性肝病临床疗效观察[J].中西医结合肝病杂志,2010,20(3)：146-148.
[29]李向阳.脂必泰胶囊治疗非酒精性脂肪性肝炎45例[J].陕西中医,2008,29(12)：1643.
[30]徐惠芬.针刺治疗非酒精性脂肪肝32例[J].浙江中医药大学学报,2007,31(6)：752-753.
[31]冯雯琪,曾志华,卓廉士.电针对非酒精性脂肪肝大鼠胰岛素抵抗的影响[J].针刺研究,2008,33(2)：111-115
[32]张荣,刘必旺,王永辉等.决明子乙酸乙酯提取物对非酒精性脂肪肝大鼠的防治 作用[J].山西中医,2009,25(7)：45-47.
[33]杨莉丽,叶红军,王慧超,等.丹参对大鼠非酒精性脂肪性肝炎和脂质代谢的作用[J].现代消化与介入治疗,2010,15(3)：144-146.
[34陈芝芸,严茂样,何蓓晖.山楂叶总黄酮防治非酒精性脂肪性肝炎的研究[J].浙江中医药大学学报,2007,31(6)：686-689.
[35]赵文霞,段荣章,苗明三,等.赤芍对大鼠脂肪肝模型胰岛素抵抗及瘦素影响的实验研究[J].四川中医,2005,23(9)：33-34.
[36]戴兆云,顾翔宇,吴一新.山豆根醋浸液治疗非酒精性脂肪性肝炎疗效初步观察[J].中国中西医结合杂志,2005,25(5)：407.
[37]丁霞,吴水生.泽泻的研究进展[J].中医药信息,2008,25(5)：19-21.
[38]韩刚,翟冠钰,董月等.姜黄素固体分散体对大鼠血脂水平的影响[J].中国老年学杂志,2009,8(29)：1936-1937.
[39]李忻,靳耀英,张韫等.柴胡皂苷防治肝病机制研究进展[J].中国中西医结合杂志,2009,29(11)：1049-1051.
[40]黎海彬,方昆阳,吕翠婷等.决明子、山楂提取物不同配比降脂作用的研究[J].中药材,2007,30(5)：537-575.
[41]金华.中药降脂研究现状[J].浙江中医学院学报,2002,26(5)：79-80.
[42]谢晶日,梁国英,李明,等.保肝消脂颗粒对非酒精性脂肪肝大鼠肝组织细胞色素P450影响的研究[J].时珍国医国药,2011,22(6)：1451-1452
[43]李红山,冯琴,胡义扬,等.祛湿化瘀方对高脂饮食诱导的大鼠肝脏脂质沉积的干预效应[J].中国中西医结合杂志.2009,29(12)：1092-1095.
[44]张昭萍,戚晓红,王瑞云,等.壳聚糖合并中药对脂肪肝治疗作用的试验研究[J].南京中医药大学学报,2001,17(2)：107-109.
[45]柳润辉,陈忠裸,徐瑞林等.胆宁片对实验性脂肪肝的保护作用.药学服务与研究[J],2007,7(3)：202-205.
[46]杨智海,黄学军等.小柴胡汤加减治疗非酒精性脂肪肝48例分析.中国基层医药[J],009,16(1)：159-160
[47]张莉,柳涛,王淼等.降脂颗粒对非酒精性脂肪肝大鼠下丘脑瘦素及瘦素受体的影响[J].中西医结合肝病杂志,2009,19(2)：89-91.
[48]古颖娴,吴谦,陈少娟,等.茵陈蒿汤对抗大鼠酒精性脂肪肝的作用[J].中国新医 药,2004,3(7)：17.
[49]夏瑾瑜,贾学平,程良斌,等.肝脂康胶囊对非酒精性脂肪肝的防治作用[J].中国中西医结合消化杂志,2004,12(1)：15.
[50]Fan JG, Farrell GC. Epidemiology of non-alcoholic fatty liver disease in China. J Hepatol,2009,50:204-210.
[51]范建高.中国非酒精性脂肪性肝病的流行病学[J].中国医师进修杂志,201 0,31(5)：4-6.
[52]Adams LA, Angulo P, Lindor KD. Nonalcoholic fatty liver disease.CMAJ, 2005,172:899-905.
[53]Utzschneider KM, Kahn SE. The Role of Insulin Resistance in Non-alcoholic Fatty Liver Disease.J Clin Endocrinol Metab,2006,12.
[54]OunossiZM, GramlichT, MatteoniCA, et al. Nonalcoholic fatty liver disease in patients with type2 diabetes[J]. ClinGastroenterol,2004,2(3):262-365.
[55]汪启迪.瘦素分泌的节律性及其影响因素[J].国外医学内科学分册,2000,27(1)：13-16.
[56]巫协宁.瘦素、肿瘤坏死因子和脂肪性肝病[J].肝脏,2002,7(4)：271-272.
[57]Karima B, Anissa I. MitoTCndrial dysfunction in NASH:Causes,consequ-ences and possible means to prevent it[J].MitoTCndrion,2006,6(1):28.
[58]李桂立,宁勇.非酒精性脂肪性肝炎发病机制初探[J].山东医学高等专科学校学报.2010,32(2)：118-120.
[59]Zeng MD,Fan JG,Lu LG,et al.Guidelines for the diagnosis and treatment of nonalcoholic fatty liver diseases.J Dig Dis,2008,9:108-112.
[60]Viollet B, Foretz M, Guigas B, et al. Activation of AMP-activated protein kinase in the liver:a new strategy for the management of metabolic hepatic disorders.J Physiol,2006,574(Pt 1):41-53.
[61]UygunA,Kadayifci A,Isik AT,et al.Metformin in the treatment of patients with non-alcohoilc steatohepatitis[J].Ailment Pharulacol Ther,2004,19:537.
[62]姚定国,叶真.罗格列酮对2型糖尿病合并非酒精性脂肪肝患者瘦素的影响[J].中国医药,2006,1(8)：457-458.
[63]曹亮,张炜.辛伐他汀治疗非酒精性脂肪肝临床观察[J].中国实用医药,2009,4(2)：144-145.
[64]中华医学会肝脏病学分会脂肪肝和酒精性肝病学组·非酒精性脂肪性肝病诊疗指南[J].中华肝脏病杂志,2006,14(3)：161-163.
[65]姜兆金,雷明君,赵艳洪.多烯磷脂酰胆碱治疗非酒精性脂肪肝疗效观察[J].传染病信息,2007,20(3)：176-177.
[66]金怒云,余小虎,施建平,等.还原型谷胱甘肽治疗非酒精性脂肪肝40例[J].临床药学,2005,14(12)：79-80.
[67]郁相云,钟建华,张旭泽.泽泻降血脂药理作用及物质基础研究[J].中国中医药现代远程教育,2010,8(11)：250.
[68]王芳.山楂叶总黄酮的药理作用[J].浙江中医药大学学掇,2010,34(2)：295-296.
[69]张明发,沈雅琴.浙贝母药理研究进展[J].上海医药,2007,28(10)：459-461.
[70]朱瑄.丹参的实验药理研究进展[J].中国现代药物应用,2010,4(15)：230-231.
[71]高艳青,刘俊.决明子的药理作用及其研究进展[J].中国药业,2008,17(8)：63-64.
[72]Feldstein AE, Papouchado BG, Angulo P, et al. Hepatic stellate cells and fibrosis progression in patients with nonalcoholic fatty liver disease[J].Clin Gastroenterol Hepatol(United States),2005,3(4):384-389.
[73]FestiD,ColecchiaA,SaccoT,etal.Hepatics steatosis in obese patients:clinical aspects and prognostic significance [J].Obesity Reviews,2004,5(1):27-35.
[74]姜玲玲,厉有名,黄伟,等.非酒精性脂肪肝及其危险因素调查[J].中国公共卫生,2005,21(3)：326-327.
[75]林小日,王昱.脂肪肝的诊治与食疗[M].广州：广东科学技术出版社,2003：25.
[76]叶传蕙.诊断学基础[M].上海：上海科学技术出版社,1995：224-225.
[77]江正辉,王泰龄.酒精性肝病[M].北京：中国医药科技出版社,2001：12-21.
[78]苏定冯,缪朝玉,王永铭.2002药理学进展[M].张树辉,丛文铭.线粒体—肿瘤诊断和治疗的靶点[M].北京：人民卫生出版社,2002,191.
[79]黄玉芳主编.病理学[M].北京：中国中医药出版社,第一版,2003：19.
[80]Day CP, James OF.Hepatic steatosis:Innocent bystander or guilty party? [J].Hepatology,1998,27:1463-1466.
[81]范建高,钟岚,王国良,等.肥胖、高脂血症致脂肪性肝炎发病机制的探讨[J].肝脏,1999,4(3)：171.
[82]GonzalezFJ,KimuraS.Study of P450 function using geneknockout and transgenic mice.Arch Biochem Biophys[J],2003,409:153 - 158.
[83]戴宁,曾民德,李继强,等.非酒精性脂肪肝肝细胞色素P450 2E1的表达与氧化抗氧化的关系[J].中华肝脏病杂志,1999,7(3)：104.5.
[84]史洪涛,陈东风,熊仁平,等.肝细胞色素P4501A1、2E1在非酒精性脂肪肝发病中的作用[J].中华消化杂志.2004,24(6)：358-360.
[85]Chalasani N,Gorskij C,Asgharn S,etal.Hepatic cytohrome P450Ⅱ E1 activity in nondiabetic patients with nonalcoholic steatohepatitis[J].Hepatology,2003,37: 544.
[86]RomicsL Jr,Kodys K,DolganiucA,et al.Diverse regulation of NF-kappaB and peroxisome proliferator-activated receptors in murine nonalcoholic fatty liver[J]. Hepatology,2004,40:376-385.
[87]Desvergne B,Wahli W. Peroxisome proliferator-activated receptors-nuclear control of metabolism[J]..Endocr Rev,1999,20:649-688.
[88]Francis GA, Annicotte JS, Auwerx J. PPAR-alpha effects on the heart and other vascular tissues[J]. Am J. Physiol Heart Circ Physiol,2003,285:H1-9.
[89]Fischer M,You M,Matsumoto, et al. Peroxisome proliferator-activated receptor alpha (PPAR alpha) agonist treatment reverses PPAR alpha dyfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice[J]. Biol Chem,2003, 278:27997-28004.
[90]Lee GY, Kim NH, Zhao ZS, et al. Peroxisome proliferator-activated receptor alpha activaties transcription of the rat hepatic malonyl-CoA decarboxytase gene: a key tegulation of malonyl-CoA level[J].Biochem,2004,378:983-990.
[91]Koh EH,Kim MS,Park JY, et al.Peroxisome proliferator-activated receptor alpha activation prevents diabetes in OLETF rats:comparison with PPAR-gamma activation[J].Diabetes,2003,52:2331-2337.
[92]LeeSS,ChanWY,LoCK,etal.J Lipid Res,2004,45:2025-2037.
[93]Nanji AA,DannenbergAJ,JokelainenK,etal.Alcoholicliver injury in the rat is assoc iated with reduced expression of peroxisome proliferator-alpha (PPARalpha)-reg ulated genes and is ameliorated by PPARalpha activation[J].Pharmacol Exp Ther, 2004,310:41-424.
[94]Clark SD.Nonalcoholic steatosis and steatohepatitis. Molecular mechanism for polyunsaturated fatty acid regulation of gene trianscription.Am.[J]Physiol Gastrontest Liver Physiol,2001,281:G865 -869.
[95]彭汉光,王萍,艾长征,等.加味四逆散对脂肪肝大鼠肝组织PPARa mRNA表达的影响[J].中国中医药信息杂志,2004,11(8)：690-691.
[96]FagerbergB,EdwardsS,HalmosT,etal.Tesaglitazar,a novel dual peroxisome proliferztor-activated receptor alpha/gamma a gonist,dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population [J].Diabetologia,2005,J u 17;[Epu bahead of print],
[97]Leuschner, U.,James,O., Dancygier,H.(Eds.),Clofibrate and other lipid-lowering drugs in he treatment of non-alcoholic steatohepatitis. Steatohepatitis(NASH and ASH). Kluwer,Dor drecht,the Netherlands[J].Laurin,2001.pp:188-196.
[98]IPE,Farrelli GC,Robertson G,etal.Central role of PPAR a dependent hepatic lipid turnover in dietary steatohepatitis in mice[J].Hepatology,2003,38:123.
[99]Reddy JK.Nonalcoholic steatosis and steatohepatitisⅢ.Peroxisomal β-oxidation, PPAR α,and steatohepatitis[J].Am J Physiol Gastrointest Liver Physiol,2001,281: G 1333.
[2]Farrell GC, Larter CZ. Nonalcoholic fatty liver disease:from steatosis to cirrhosis.Hepatology,2006,43(2Suppl1):S99-S112.
[3]de Alwis NM. Day CP. Non-alcoholic fatty liver disease:the mist gradually clears. J Hepatol.2008,48 Suppl 1:S104-S112.
[4]Angulo P.GI epidemiology:nonalcoholic fatty liver disease [J].Aliment Pharmacol Ther,2007,25(8):883-889.
[5]Fan JG,Li F,Cai XB,et al.The importance of metabolic factors for the increasing prevalence of fatty liver in shanghai factory workers[J].J Gastroenterol Hepatol,2007,22(5):663-558.
[6]赵文霞,段荣章,刘君颖.1163例非酒精性脂肪肝患者与气虚质痰湿质相关性研究[J].辽宁中医杂志,2010,37(8)：1543-1544.
[7]张慧,胡义扬.肿瘤坏死因子α、脂联素与非酒精性脂肪性肝病[J].肝脏,2006,11(2)：137-139.
[8]曾民德.脂肪肝发病机制及其二次打击假设[J].中华消化杂志,2002,22(3)：167-168.
[9]杨建辉.林鹤和治脂肪肝的经验[J].江西中医药,2006,31(3)：1-2.
[10]王天明.赵国荣教授治疗脂肪肝经验[J].湖南中医杂志,2006,22(3)：42.
[11]周琪,刘鉴.李军教授从痰瘀论治脂肪肝临床经验探要[J].实用中医内科杂志,2008,22(1)：15-16.
[12]胡怀强,周永红,范玉芹.王新陆教授从浊论治脂肪肝经验撷著[J].中华中医药学刊,2007,25(9)：1781-1782.
[13]党中勤.十味肝脂康胶囊治疗脂肪肝62例[J].陕西中医,2003,24(7)：589.
[14]叶未设.中医对脂肪肝的认识及防治[J].中国热带医学,2004,4(6)：1023.
[15]韩加强,孟庆敏.脂肪肝的辨证论治[J].亚太传统医药,2007,3(2)：62.
[16]陈妹娴,应爱兰,辨证分型治疗脂肪肝探识[J].实用中医内科杂志,2006,20(4)：384.
[17]林艳,于敏,田谧,等.辨证治疗脂肪肝112例[J].中国中医急症,2007,16(8)： 1000-1001.
[18]陈腾云,何敏.脂肪肝中医辨证论治体会[J].中国误诊学杂志,2005,5(13)：2550-2551.
[19]李少东,李红山,冯琴,等.脂肪肝中医证型分类的文献分析[J].中西医结合肝病杂志,2006,16(4)：255-257.
[20]李玉权,杨钦河,谢维宁,等.疏肝健脾法治疗非酒精性脂肪肝35例[J].中医杂志,2007,48(9)：824-825.
[21]黄志平,林燕萍,张萍,等.茵陈越鞠汤治疗非酒精性脂肪性肝炎的临床观察[J].中华中医药学刊,2008,26,(5)：1100-1101.
[22]石拓,叶勇,时昭红,等.化痰活血方治疗高脂非酒精性脂肪肝患者50例[J].中国中西医结合消化杂志,2007,15(5)：344-345.
[23]谢立芳.“益气活血方”治疗非酒精性脂肪性肝病患者28例[J].江苏中医药,2010,42(4)：39.
[24]张卫星,吴忆东.补肝肾法治疗2型糖尿病性非酒精性脂肪肝50例[J].浙江中医杂志.2009,44(4).269.
[25]黄欣,张哲永.当飞利肝宁胶囊治疗非酒精性脂肪性肝病32例临床观察[J].中医杂志,2007,48(6)：524-525.
[26]程勇,赵亚敏,苏剑,等.水飞蓟宾胶囊对非酒精性脂肪性肝炎患者血清IL-18、IL-8、TNF-α、肝酶及血脂的影响[J].中国老年学杂志,2010,30(7)：979-980.
[27]赵文霞,张玉禄.消脂护肝胶囊对非酒精性脂肪肝患者胰岛素抵抗及瘦素水平的影响[J].中医研究,2005,18(5)：21-23.
[28]闫妍,徐亮,宓余强.壳脂胶囊治疗非酒精性脂肪性肝病临床疗效观察[J].中西医结合肝病杂志,2010,20(3)：146-148.
[29]李向阳.脂必泰胶囊治疗非酒精性脂肪性肝炎45例[J].陕西中医,2008,29(12)：1643.
[30]徐惠芬.针刺治疗非酒精性脂肪肝32例[J].浙江中医药大学学报,2007,31(6)：752-753.
[31]冯雯琪,曾志华,卓廉士.电针对非酒精性脂肪肝大鼠胰岛素抵抗的影响[J].针刺研究,2008,33(2)：111-115
[32]张荣,刘必旺,王永辉等.决明子乙酸乙酯提取物对非酒精性脂肪肝大鼠的防治 作用[J].山西中医,2009,25(7)：45-47.
[33]杨莉丽,叶红军,王慧超,等.丹参对大鼠非酒精性脂肪性肝炎和脂质代谢的作用[J].现代消化与介入治疗,2010,15(3)：144-146.
[34陈芝芸,严茂样,何蓓晖.山楂叶总黄酮防治非酒精性脂肪性肝炎的研究[J].浙江中医药大学学报,2007,31(6)：686-689.
[35]赵文霞,段荣章,苗明三,等.赤芍对大鼠脂肪肝模型胰岛素抵抗及瘦素影响的实验研究[J].四川中医,2005,23(9)：33-34.
[36]戴兆云,顾翔宇,吴一新.山豆根醋浸液治疗非酒精性脂肪性肝炎疗效初步观察[J].中国中西医结合杂志,2005,25(5)：407.
[37]丁霞,吴水生.泽泻的研究进展[J].中医药信息,2008,25(5)：19-21.
[38]韩刚,翟冠钰,董月等.姜黄素固体分散体对大鼠血脂水平的影响[J].中国老年学杂志,2009,8(29)：1936-1937.
[39]李忻,靳耀英,张韫等.柴胡皂苷防治肝病机制研究进展[J].中国中西医结合杂志,2009,29(11)：1049-1051.
[40]黎海彬,方昆阳,吕翠婷等.决明子、山楂提取物不同配比降脂作用的研究[J].中药材,2007,30(5)：537-575.
[41]金华.中药降脂研究现状[J].浙江中医学院学报,2002,26(5)：79-80.
[42]谢晶日,梁国英,李明,等.保肝消脂颗粒对非酒精性脂肪肝大鼠肝组织细胞色素P450影响的研究[J].时珍国医国药,2011,22(6)：1451-1452
[43]李红山,冯琴,胡义扬,等.祛湿化瘀方对高脂饮食诱导的大鼠肝脏脂质沉积的干预效应[J].中国中西医结合杂志.2009,29(12)：1092-1095.
[44]张昭萍,戚晓红,王瑞云,等.壳聚糖合并中药对脂肪肝治疗作用的试验研究[J].南京中医药大学学报,2001,17(2)：107-109.
[45]柳润辉,陈忠裸,徐瑞林等.胆宁片对实验性脂肪肝的保护作用.药学服务与研究[J],2007,7(3)：202-205.
[46]杨智海,黄学军等.小柴胡汤加减治疗非酒精性脂肪肝48例分析.中国基层医药[J],009,16(1)：159-160
[47]张莉,柳涛,王淼等.降脂颗粒对非酒精性脂肪肝大鼠下丘脑瘦素及瘦素受体的影响[J].中西医结合肝病杂志,2009,19(2)：89-91.
[48]古颖娴,吴谦,陈少娟,等.茵陈蒿汤对抗大鼠酒精性脂肪肝的作用[J].中国新医 药,2004,3(7)：17.
[49]夏瑾瑜,贾学平,程良斌,等.肝脂康胶囊对非酒精性脂肪肝的防治作用[J].中国中西医结合消化杂志,2004,12(1)：15.
[50]Fan JG, Farrell GC. Epidemiology of non-alcoholic fatty liver disease in China. J Hepatol,2009,50:204-210.
[51]范建高.中国非酒精性脂肪性肝病的流行病学[J].中国医师进修杂志,201 0,31(5)：4-6.
[52]Adams LA, Angulo P, Lindor KD. Nonalcoholic fatty liver disease.CMAJ, 2005,172:899-905.
[53]Utzschneider KM, Kahn SE. The Role of Insulin Resistance in Non-alcoholic Fatty Liver Disease.J Clin Endocrinol Metab,2006,12.
[54]OunossiZM, GramlichT, MatteoniCA, et al. Nonalcoholic fatty liver disease in patients with type2 diabetes[J]. ClinGastroenterol,2004,2(3):262-365.
[55]汪启迪.瘦素分泌的节律性及其影响因素[J].国外医学内科学分册,2000,27(1)：13-16.
[56]巫协宁.瘦素、肿瘤坏死因子和脂肪性肝病[J].肝脏,2002,7(4)：271-272.
[57]Karima B, Anissa I. MitoTCndrial dysfunction in NASH:Causes,consequ-ences and possible means to prevent it[J].MitoTCndrion,2006,6(1):28.
[58]李桂立,宁勇.非酒精性脂肪性肝炎发病机制初探[J].山东医学高等专科学校学报.2010,32(2)：118-120.
[59]Zeng MD,Fan JG,Lu LG,et al.Guidelines for the diagnosis and treatment of nonalcoholic fatty liver diseases.J Dig Dis,2008,9:108-112.
[60]Viollet B, Foretz M, Guigas B, et al. Activation of AMP-activated protein kinase in the liver:a new strategy for the management of metabolic hepatic disorders.J Physiol,2006,574(Pt 1):41-53.
[61]UygunA,Kadayifci A,Isik AT,et al.Metformin in the treatment of patients with non-alcohoilc steatohepatitis[J].Ailment Pharulacol Ther,2004,19:537.
[62]姚定国,叶真.罗格列酮对2型糖尿病合并非酒精性脂肪肝患者瘦素的影响[J].中国医药,2006,1(8)：457-458.
[63]曹亮,张炜.辛伐他汀治疗非酒精性脂肪肝临床观察[J].中国实用医药,2009,4(2)：144-145.
[64]中华医学会肝脏病学分会脂肪肝和酒精性肝病学组·非酒精性脂肪性肝病诊疗指南[J].中华肝脏病杂志,2006,14(3)：161-163.
[65]姜兆金,雷明君,赵艳洪.多烯磷脂酰胆碱治疗非酒精性脂肪肝疗效观察[J].传染病信息,2007,20(3)：176-177.
[66]金怒云,余小虎,施建平,等.还原型谷胱甘肽治疗非酒精性脂肪肝40例[J].临床药学,2005,14(12)：79-80.
[67]郁相云,钟建华,张旭泽.泽泻降血脂药理作用及物质基础研究[J].中国中医药现代远程教育,2010,8(11)：250.
[68]王芳.山楂叶总黄酮的药理作用[J].浙江中医药大学学掇,2010,34(2)：295-296.
[69]张明发,沈雅琴.浙贝母药理研究进展[J].上海医药,2007,28(10)：459-461.
[70]朱瑄.丹参的实验药理研究进展[J].中国现代药物应用,2010,4(15)：230-231.
[71]高艳青,刘俊.决明子的药理作用及其研究进展[J].中国药业,2008,17(8)：63-64.
[72]Feldstein AE, Papouchado BG, Angulo P, et al. Hepatic stellate cells and fibrosis progression in patients with nonalcoholic fatty liver disease[J].Clin Gastroenterol Hepatol(United States),2005,3(4):384-389.
[73]FestiD,ColecchiaA,SaccoT,etal.Hepatics steatosis in obese patients:clinical aspects and prognostic significance [J].Obesity Reviews,2004,5(1):27-35.
[74]姜玲玲,厉有名,黄伟,等.非酒精性脂肪肝及其危险因素调查[J].中国公共卫生,2005,21(3)：326-327.
[75]林小日,王昱.脂肪肝的诊治与食疗[M].广州：广东科学技术出版社,2003：25.
[76]叶传蕙.诊断学基础[M].上海：上海科学技术出版社,1995：224-225.
[77]江正辉,王泰龄.酒精性肝病[M].北京：中国医药科技出版社,2001：12-21.
[78]苏定冯,缪朝玉,王永铭.2002药理学进展[M].张树辉,丛文铭.线粒体—肿瘤诊断和治疗的靶点[M].北京：人民卫生出版社,2002,191.
[79]黄玉芳主编.病理学[M].北京：中国中医药出版社,第一版,2003：19.
[80]Day CP, James OF.Hepatic steatosis:Innocent bystander or guilty party? [J].Hepatology,1998,27:1463-1466.
[81]范建高,钟岚,王国良,等.肥胖、高脂血症致脂肪性肝炎发病机制的探讨[J].肝脏,1999,4(3)：171.
[82]GonzalezFJ,KimuraS.Study of P450 function using geneknockout and transgenic mice.Arch Biochem Biophys[J],2003,409:153 - 158.
[83]戴宁,曾民德,李继强,等.非酒精性脂肪肝肝细胞色素P450 2E1的表达与氧化抗氧化的关系[J].中华肝脏病杂志,1999,7(3)：104.5.
[84]史洪涛,陈东风,熊仁平,等.肝细胞色素P4501A1、2E1在非酒精性脂肪肝发病中的作用[J].中华消化杂志.2004,24(6)：358-360.
[85]Chalasani N,Gorskij C,Asgharn S,etal.Hepatic cytohrome P450Ⅱ E1 activity in nondiabetic patients with nonalcoholic steatohepatitis[J].Hepatology,2003,37: 544.
[86]RomicsL Jr,Kodys K,DolganiucA,et al.Diverse regulation of NF-kappaB and peroxisome proliferator-activated receptors in murine nonalcoholic fatty liver[J]. Hepatology,2004,40:376-385.
[87]Desvergne B,Wahli W. Peroxisome proliferator-activated receptors-nuclear control of metabolism[J]..Endocr Rev,1999,20:649-688.
[88]Francis GA, Annicotte JS, Auwerx J. PPAR-alpha effects on the heart and other vascular tissues[J]. Am J. Physiol Heart Circ Physiol,2003,285:H1-9.
[89]Fischer M,You M,Matsumoto, et al. Peroxisome proliferator-activated receptor alpha (PPAR alpha) agonist treatment reverses PPAR alpha dyfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice[J]. Biol Chem,2003, 278:27997-28004.
[90]Lee GY, Kim NH, Zhao ZS, et al. Peroxisome proliferator-activated receptor alpha activaties transcription of the rat hepatic malonyl-CoA decarboxytase gene: a key tegulation of malonyl-CoA level[J].Biochem,2004,378:983-990.
[91]Koh EH,Kim MS,Park JY, et al.Peroxisome proliferator-activated receptor alpha activation prevents diabetes in OLETF rats:comparison with PPAR-gamma activation[J].Diabetes,2003,52:2331-2337.
[92]LeeSS,ChanWY,LoCK,etal.J Lipid Res,2004,45:2025-2037.
[93]Nanji AA,DannenbergAJ,JokelainenK,etal.Alcoholicliver injury in the rat is assoc iated with reduced expression of peroxisome proliferator-alpha (PPARalpha)-reg ulated genes and is ameliorated by PPARalpha activation[J].Pharmacol Exp Ther, 2004,310:41-424.
[94]Clark SD.Nonalcoholic steatosis and steatohepatitis. Molecular mechanism for polyunsaturated fatty acid regulation of gene trianscription.Am.[J]Physiol Gastrontest Liver Physiol,2001,281:G865 -869.
[95]彭汉光,王萍,艾长征,等.加味四逆散对脂肪肝大鼠肝组织PPARa mRNA表达的影响[J].中国中医药信息杂志,2004,11(8)：690-691.
[96]FagerbergB,EdwardsS,HalmosT,etal.Tesaglitazar,a novel dual peroxisome proliferztor-activated receptor alpha/gamma a gonist,dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population [J].Diabetologia,2005,J u 17;[Epu bahead of print],
[97]Leuschner, U.,James,O., Dancygier,H.(Eds.),Clofibrate and other lipid-lowering drugs in he treatment of non-alcoholic steatohepatitis. Steatohepatitis(NASH and ASH). Kluwer,Dor drecht,the Netherlands[J].Laurin,2001.pp:188-196.
[98]IPE,Farrelli GC,Robertson G,etal.Central role of PPAR a dependent hepatic lipid turnover in dietary steatohepatitis in mice[J].Hepatology,2003,38:123.
[99]Reddy JK.Nonalcoholic steatosis and steatohepatitisⅢ.Peroxisomal β-oxidation, PPAR α,and steatohepatitis[J].Am J Physiol Gastrointest Liver Physiol,2001,281: G 1333.