固醇调节元件结合蛋白1(Sterol regulatory element-binding protein 1,SREBP-1)是重要的核转录因子之一,能调控内源性胆固醇、脂肪酸、甘油三酯和磷脂合成所需酶的表达,以维持血脂动态平衡。研究表明,SREBP-1及其靶基因网络的异常可引...固醇调节元件结合蛋白1(Sterol regulatory element-binding protein 1,SREBP-1)是重要的核转录因子之一,能调控内源性胆固醇、脂肪酸、甘油三酯和磷脂合成所需酶的表达,以维持血脂动态平衡。研究表明,SREBP-1及其靶基因网络的异常可引起胰岛素抵抗、Ⅱ型糖尿病、心功能紊乱、血管并发症和肝脂肪变等一系列代谢性疾病。近年高通量组学技术的发展极大扩展了对SREBP-1靶基因及其转录调控模式的了解。文章对SREBP-1蛋白结构、活化过程、DNA结合位点及其调控的靶基因等方面的研究进展进行了综述,并着重介绍了基于组学数据的转录调控网络的构建,这将有助于更好的认识SREBP-1在脂类代谢中的作用,为深入探讨脂质代谢性疾病的治疗提供新线索。展开更多
Background Statin therapy has affected glucose homoeostasis of type 2 diabetes patients,which could be related with bile acids metabolism.Whether bile acid metabolism and the expression of farnesoid X receptor （FXR）...Background Statin therapy has affected glucose homoeostasis of type 2 diabetes patients,which could be related with bile acids metabolism.Whether bile acid metabolism and the expression of farnesoid X receptor （FXR）,liver X receptor-α （LXR-α） and sterol regulatory element-binding protein （Srebp）-1c is regulated by hyperglycemia,or whether simvastatin therapy led to higher glucose is related with down-regulated expression of FXR in diabetic rats remained unclear.Methods Forty male Wistar rats were randomly divided into four groups：normal control rats,insulin resistance rats,diabetic model rats,and the late simvastatin induced diabetic rats.Normal control rats were fed with standard diet,others were fed with high-fat diet.Diabetic model rats were induced by a single intraperitoneal injection of streptozotocin （STZ）.The late simvastatin induced diabetic rats started simvastatin administration after STZ induced diabetic model rats.Characteristics of fasting blood glucose （FPG）,lipid files and total bile acids （TBAs） were measured and the oral glucose tolerance test （OGTT） was performed after overnight fasting at the eighth weekend.RNA and protein levels of FXR,LXR-α and Srebp-1c were tested by Western blotting and reverse transcription polymerase chain reaction （RT-PCR）.Results The insulin resistance rats showed higher glucose,lipid files and lower expression of FXR compared with normal control rats （P ＞0.05）.The diabetic model rats showed significantly higher glucose,lipid files,TBA and lower expression of FXR compared with insulin resistance rats （P ＜0.05）.The late simvastatin induced diabetic rats displayed higher glucose and TBA and lower expression of FXR compared with diabetic model rats （P ＜0.05）.Conclusions Changes in bile acid homeostasis,including the alterations of bile acid levels and bile acid receptors,are either a cause or a consequence of the metabolic disturbances observed during diabetic models.Statin therapy induced hyperglycemia may be related展开更多
目的探讨单磷酸腺苷活化蛋白激酶(adenosine monophosphate-activated protein kinase,AMPK)在低剂量二乙基亚硝胺(diethylnitrosamine,DEN)合并高脂饮食诱导的大鼠肝癌前病变发生中的作用及其机制。方法体内实验采用腹腔注射DEN(30 mg/...目的探讨单磷酸腺苷活化蛋白激酶(adenosine monophosphate-activated protein kinase,AMPK)在低剂量二乙基亚硝胺(diethylnitrosamine,DEN)合并高脂饮食诱导的大鼠肝癌前病变发生中的作用及其机制。方法体内实验采用腹腔注射DEN(30 mg/kg)合并高脂饮食饲喂大鼠16周诱导肝癌前病变模型,通过HE染色、Western blotting、Real-time PCR、免疫组织化学等方法观察谷胱甘肽S转移酶(glutathione S-transferase-π,GST-π)、固醇调节元件结合蛋白1c(sterol regulatory element binding protein-1c,SREBP-1c)、脂肪酸合成酶(fatty acid synthase,FAS)、乙酰辅酶A羧化酶(acetyl-Co A carboxylase,ACC)、硬脂酰辅酶A去饱和酶1(stearoyl-Co A desaturase 1,SCD1)及AMPK、p-AMPK的表达变化;体外实验观察AMPK对棕榈酸(palmitic acid,PA)诱导的大鼠H4IIE细胞脂质代谢的影响。结果与单纯DEN处理组比较,DEN+高脂组大鼠肝细胞脂肪变性、气球样变、伴有炎性细胞浸润及小灶性坏死;GST-π表达水平增高;三酰甘油(triglyceride,TG)及SREBP-1c、FAS、ACC、SCD1表达水平上升;p-AMPK水平下降。AMPK通过抑制SREBP-1c的表达水平降低棕榈酸诱导的H4IIE细胞内脂质合成。结论 AMPK可能通过抑制SREBP-1c的表达水平参与大鼠肝癌前病变的形成。展开更多
文摘固醇调节元件结合蛋白1(Sterol regulatory element-binding protein 1,SREBP-1)是重要的核转录因子之一,能调控内源性胆固醇、脂肪酸、甘油三酯和磷脂合成所需酶的表达,以维持血脂动态平衡。研究表明,SREBP-1及其靶基因网络的异常可引起胰岛素抵抗、Ⅱ型糖尿病、心功能紊乱、血管并发症和肝脂肪变等一系列代谢性疾病。近年高通量组学技术的发展极大扩展了对SREBP-1靶基因及其转录调控模式的了解。文章对SREBP-1蛋白结构、活化过程、DNA结合位点及其调控的靶基因等方面的研究进展进行了综述,并着重介绍了基于组学数据的转录调控网络的构建,这将有助于更好的认识SREBP-1在脂类代谢中的作用,为深入探讨脂质代谢性疾病的治疗提供新线索。
基金This work was supported by grants from the National Natural Science Foundation of China （Nos. 81170771, 81101183 and 81270175）, Science and Technology Development Programme of Shandong （No. 2012GSF 11803）, International Cooperation Programme of 3inan City （No. 201011008）.Acknowledgements： We thank Han Jing, Lu Yong and Jiang Qiang for their assistance in animal experiment.
文摘Background Statin therapy has affected glucose homoeostasis of type 2 diabetes patients,which could be related with bile acids metabolism.Whether bile acid metabolism and the expression of farnesoid X receptor （FXR）,liver X receptor-α （LXR-α） and sterol regulatory element-binding protein （Srebp）-1c is regulated by hyperglycemia,or whether simvastatin therapy led to higher glucose is related with down-regulated expression of FXR in diabetic rats remained unclear.Methods Forty male Wistar rats were randomly divided into four groups：normal control rats,insulin resistance rats,diabetic model rats,and the late simvastatin induced diabetic rats.Normal control rats were fed with standard diet,others were fed with high-fat diet.Diabetic model rats were induced by a single intraperitoneal injection of streptozotocin （STZ）.The late simvastatin induced diabetic rats started simvastatin administration after STZ induced diabetic model rats.Characteristics of fasting blood glucose （FPG）,lipid files and total bile acids （TBAs） were measured and the oral glucose tolerance test （OGTT） was performed after overnight fasting at the eighth weekend.RNA and protein levels of FXR,LXR-α and Srebp-1c were tested by Western blotting and reverse transcription polymerase chain reaction （RT-PCR）.Results The insulin resistance rats showed higher glucose,lipid files and lower expression of FXR compared with normal control rats （P ＞0.05）.The diabetic model rats showed significantly higher glucose,lipid files,TBA and lower expression of FXR compared with insulin resistance rats （P ＜0.05）.The late simvastatin induced diabetic rats displayed higher glucose and TBA and lower expression of FXR compared with diabetic model rats （P ＜0.05）.Conclusions Changes in bile acid homeostasis,including the alterations of bile acid levels and bile acid receptors,are either a cause or a consequence of the metabolic disturbances observed during diabetic models.Statin therapy induced hyperglycemia may be related
