探究鸠坑龙井茶水提物(LJT)对小鼠肝组织脂质代谢SREBPs通路信号影响及肠道菌群的调节作用。通过高脂饮食诱导小鼠构建非酒精性脂肪肝(NAFL)模型,并给予LJT(300 mg·kg^(-1))灌胃干预。定期记录小鼠的体质量,检测小鼠血清生化指标...探究鸠坑龙井茶水提物(LJT)对小鼠肝组织脂质代谢SREBPs通路信号影响及肠道菌群的调节作用。通过高脂饮食诱导小鼠构建非酒精性脂肪肝(NAFL)模型,并给予LJT(300 mg·kg^(-1))灌胃干预。定期记录小鼠的体质量,检测小鼠血清生化指标和葡萄糖耐受水平,观察并分析Hematoxylin-Eosin(HE)染色、油红O染色肝组织切片特征;应用Real-time qPCR技术检测小鼠肝组织SREBPs通路7个基因(SREBP-1c、FAS、SCD-1、ACC-1、SREBP-2、HMGCR、PPARγ)的相对表达量,采用蛋白免疫印记技术(Western Blot)分析肝组织蛋白质表达水平,同时对小鼠肠道菌群进行高通量测序(16 S rDNA)并分析其结构。结果显示,LJT干预后小鼠体质量、血糖AUC、血清TG、TC、LDL-C和肝脏中TG、TC水平有显著下降,龙井组小鼠肝组织SREBP-1c、FAS、ACC-1、SCD-1和PPARγ蛋白表达水平降低,SREBP-1c、SCD-1、FAS、ACC-1、SREBP-2、HMGCR、PPARγ基因的相对表达量显著下调;16 S rDNA分析发现,小鼠肠道菌群门水平主要为Firmicutes、Bacteroidota、Desulfobacterota和Actinobacteriota 4类,LJT有效延缓了高脂饮食引起的Firmicutes相对丰度升高和Bacteroidota相对丰度下降趋势,并增加了肠道菌群的物种丰度。结果表明,LJT能够干预小鼠肝脂肪变性SREBPs通路信号表达,改善小鼠肠道菌群紊乱,具有降脂减肥作用。展开更多
As a culinary and medicinal herb, rosemary is widely used. The present work aimed to investigate the effects of rosemary extracts on metabolic diseases and the underlying mechanisms of action. Liver cells stably expre...As a culinary and medicinal herb, rosemary is widely used. The present work aimed to investigate the effects of rosemary extracts on metabolic diseases and the underlying mechanisms of action. Liver cells stably expressing SREBP reporter were used to evaluate the inhibitory effects of different fractions of rosemary extracts on SREBP activity. The obese mice induced by Western-type diet were orally administered with rosemary extracts or vehicle for 7 weeks, the plasma and tissue lipids were analyzed. SREBPs and their target genes were measured by quantitative RT-PCR. We demonstrated that the petroleum ether sub-fraction of rosemary extracts(PER) exhibited the best activity in regulating lipid metabolism by inhibiting SREBPs, while water and n-Bu OH sub-fraction showed the SREBPs agonist-effect. After PER treatment, there was a significant reduction of total SREBPs in liver cells. PER not only decreased SREBPs nuclear abundance, but also inhibited their activity, resulting in decreased expression of SREBP-1c and SREBP-2 target genes in vitro and in vivo. Inhibiting SREBPs by PER decreased the total triglycerides and cholesterol contents of the liver cells. In the mice fed with Western-type diet, PER treatment decreased TG, TC, ALT, glucose, and insulin in blood, and improved glucose tolerance and insulin sensitivity. Furthermore, PER treatment also decreased lipid contents in liver, brown adipose tissue, and white adipose tissue. Our results from the present study suggested that petroleum ether fraction of rosemary extracts exhibited the best potential of improving lipid metabolism by inhibiting SREBPs activity.展开更多
茶叶可调节不同组织的脂质代谢,抑制肠道消化吸收脂质,起到降脂减肥作用。茶叶对脂质代谢途径具有显著影响,主要通过调控固醇调节元件结合蛋白(Sterol Regulatory Element Binding Proteins)及其上下游因子表达,影响脂质合成和分解,从...茶叶可调节不同组织的脂质代谢,抑制肠道消化吸收脂质,起到降脂减肥作用。茶叶对脂质代谢途径具有显著影响,主要通过调控固醇调节元件结合蛋白(Sterol Regulatory Element Binding Proteins)及其上下游因子表达,影响脂质合成和分解,从而降低脂肪积累。展开更多
YdjC chitooligosaccharide deacetylase homolog(YDJC)has been identified as a susceptibility gene for inflammatory bowel disease(IBD),yet its role in the pathogenesis of IBD,particularly in regulating immune responses i...YdjC chitooligosaccharide deacetylase homolog(YDJC)has been identified as a susceptibility gene for inflammatory bowel disease(IBD),yet its role in the pathogenesis of IBD,particularly in regulating immune responses in the gut mucosa,remains elusive.In this study,we demonstrated that YDJC expression is downregulated in inflamed mucosa,particularly in the CD4^(+)T cells of IBD patients,and that Ydjc deficiency promotes CD4^(+)T-cell proliferation and Th1 cell differentiation,thereby exacerbating acute and chronic colitis in mice.Integrative transcriptomic,proteomic,and metabolomic analyses revealed that Ydjc^(-/-)CD4^(+)T cells exhibit upregulated SREBP2-mediated cholesterol biosynthesis.Consistently,treatment with key enzyme inhibitors targeting cholesterol biosynthesis,including simvastatin,fatostatin,and AAV-sh-Srebf2,markedly suppressed CD4^(+)T-cell proliferation and Th1 cell differentiation,thereby alleviating colitis in Ydjc^(-/-)mice.Mechanistically,YDJC directly deacetylates SREBP2,which further suppresses downstream target gene expression(e.g.,Hmgcr,Hmgcs1,and Cyp51).Therefore,our findings elucidate a novel mechanism whereby YDJC restrains intestinal mucosal inflammation by downregulating SREBP2-driven Th1 cell differentiation,suggesting that targeting YDJC and SREBP2-mediated cholesterol biosynthesis may serve as promising therapeutic strategies for IBD.展开更多
Sterol regulator element binding proteins(SREBPs)are a family of transcription factors involved in the biogenesis of cholesterol,fatty acids and triglycerides.They also regulate physiological functions of many organs,...Sterol regulator element binding proteins(SREBPs)are a family of transcription factors involved in the biogenesis of cholesterol,fatty acids and triglycerides.They also regulate physiological functions of many organs,such as thyroid,brain,heart,pancreas and hormone synthesis.Beside the physiological effects,SREBPs participate in some pathological processes,diabetes,endoplasmic reticulum stress,atherosclerosis and chronic kidney disease associated with SREBP expression changes.In the liver,SREBPs are involved in the pathogenesis of nonalcoholic fatty liver disease,nonalcoholic steatohepatitis,hepatitis and hepatic cancer.There are several SREBP inhibitors that have potential for treating obesity,diabetes and cancer.This review assesses the recent findings about the roles of SREBPs in the physiology of organs'function and pathogenesis of liver diseases.展开更多
The mammalian target of rapamycin(mTOR)-sterol regulatory element-binding proteins(SREBPs)signaling promotes lipogenesis.However,mTOR inhibitors also displayed a significant side effect of hyperlipidemia.Thus,it is es...The mammalian target of rapamycin(mTOR)-sterol regulatory element-binding proteins(SREBPs)signaling promotes lipogenesis.However,mTOR inhibitors also displayed a significant side effect of hyperlipidemia.Thus,it is essential to develop mTOR-specific inhibitors to inhibit lipogenesis.Here,we screened the endogenous inhibitors of mTOR,and identified that FKBP38 as a vital regulator of lipid metabolism.FKBP38 decreased the lipid content in vitro and in vivo via suppression of the mTOR/P70 S6 K/SREBPs pathway.3,5,6,7,8,3’,4’-Heptamethoxyflavone(HMF),a citrus flavonoid,was found to target FKBP38 to suppress the mTOR/P70 S6 K/SREBPs pathway,reduce lipid level,and potently ameliorate hyperlipidemia and insulin resistance in high fat diet(HFD)-fed mice.Our findings suggest that pharmacological intervention by targeting FKBP38 to suppress mTOR/P70 S6 K/SREBPs pathway is a potential therapeutic strategy for hyperlipidemia,and HMF could be a leading compound for development of anti-hyperlipidemia drugs.展开更多
目的探讨前列腺癌组织中固醇调节元件结合蛋白1(SREBP1)、乙酰辅酶A羧化酶α(ACCα)的表达及对前列腺癌细胞系DU145增殖、迁移和侵袭的影响。方法通过在线网站TIMER、UALCAN、GEPIA和THE HUMAN PROTEIN ATLAS分析SREBP1和ACCα在前列腺...目的探讨前列腺癌组织中固醇调节元件结合蛋白1(SREBP1)、乙酰辅酶A羧化酶α(ACCα)的表达及对前列腺癌细胞系DU145增殖、迁移和侵袭的影响。方法通过在线网站TIMER、UALCAN、GEPIA和THE HUMAN PROTEIN ATLAS分析SREBP1和ACCα在前列腺癌中表达情况。收集合肥医科大学第五附属(珠海)医院2016年1月至2018年12月期间收治的58例前列腺癌(PCa)和58例良性前列腺增生(BPH)患者石蜡标本,采用免疫组织化学法检测上述组织中SREBP1和ACCα的表达;采用shRNA下调DU145细胞中SREBP1的表达后,qRT-PCR检测ACCα的表达变化;采用CCK-8法检测细胞增殖能力;流式细胞仪检测细胞周期分布;Western blot实验检测SREBP1和ACCα的表达;通过Transwell迁移和侵袭实验检测沉默SREBP1后DU145细胞迁移和侵袭的变化;细胞划痕愈合实验检测干扰SREBP1后对DU145细胞划痕愈合能力的影响;EdU实验检测沉默SREBP1表达后细胞增殖能力;通过油红O染色,观察干扰SREBP1的表达后,前列腺癌细胞中脂质含量变化。结果TIMER、UALCAN在线数据库分析发现,同正常前列腺组织相比,ACCα在前列腺癌中表达显著升高(P<0.001)。沉默SREBP1后,DU145细胞增殖、迁移和侵袭能力均较对照组显著降低(P<0.01);流式细胞术检测沉默SREBP1后DU145细胞发生G1期阻滞(P<0.01)。SREBP1敲低后前列腺癌细胞中脂肪含量显著降低(P<0.01)。结论SREBP1可能通过调控ACCα的表达,促进前列腺癌细胞增殖、迁移和侵袭。展开更多
文摘探究鸠坑龙井茶水提物(LJT)对小鼠肝组织脂质代谢SREBPs通路信号影响及肠道菌群的调节作用。通过高脂饮食诱导小鼠构建非酒精性脂肪肝(NAFL)模型,并给予LJT(300 mg·kg^(-1))灌胃干预。定期记录小鼠的体质量,检测小鼠血清生化指标和葡萄糖耐受水平,观察并分析Hematoxylin-Eosin(HE)染色、油红O染色肝组织切片特征;应用Real-time qPCR技术检测小鼠肝组织SREBPs通路7个基因(SREBP-1c、FAS、SCD-1、ACC-1、SREBP-2、HMGCR、PPARγ)的相对表达量,采用蛋白免疫印记技术(Western Blot)分析肝组织蛋白质表达水平,同时对小鼠肠道菌群进行高通量测序(16 S rDNA)并分析其结构。结果显示,LJT干预后小鼠体质量、血糖AUC、血清TG、TC、LDL-C和肝脏中TG、TC水平有显著下降,龙井组小鼠肝组织SREBP-1c、FAS、ACC-1、SCD-1和PPARγ蛋白表达水平降低,SREBP-1c、SCD-1、FAS、ACC-1、SREBP-2、HMGCR、PPARγ基因的相对表达量显著下调;16 S rDNA分析发现,小鼠肠道菌群门水平主要为Firmicutes、Bacteroidota、Desulfobacterota和Actinobacteriota 4类,LJT有效延缓了高脂饮食引起的Firmicutes相对丰度升高和Bacteroidota相对丰度下降趋势,并增加了肠道菌群的物种丰度。结果表明,LJT能够干预小鼠肝脂肪变性SREBPs通路信号表达,改善小鼠肠道菌群紊乱,具有降脂减肥作用。
基金supported by the Funds for Creative Research Groups of ChinaNational Natural Science Foundation of China(No.81421005)National Natural Science Foundation of China(No.81274159)
文摘As a culinary and medicinal herb, rosemary is widely used. The present work aimed to investigate the effects of rosemary extracts on metabolic diseases and the underlying mechanisms of action. Liver cells stably expressing SREBP reporter were used to evaluate the inhibitory effects of different fractions of rosemary extracts on SREBP activity. The obese mice induced by Western-type diet were orally administered with rosemary extracts or vehicle for 7 weeks, the plasma and tissue lipids were analyzed. SREBPs and their target genes were measured by quantitative RT-PCR. We demonstrated that the petroleum ether sub-fraction of rosemary extracts(PER) exhibited the best activity in regulating lipid metabolism by inhibiting SREBPs, while water and n-Bu OH sub-fraction showed the SREBPs agonist-effect. After PER treatment, there was a significant reduction of total SREBPs in liver cells. PER not only decreased SREBPs nuclear abundance, but also inhibited their activity, resulting in decreased expression of SREBP-1c and SREBP-2 target genes in vitro and in vivo. Inhibiting SREBPs by PER decreased the total triglycerides and cholesterol contents of the liver cells. In the mice fed with Western-type diet, PER treatment decreased TG, TC, ALT, glucose, and insulin in blood, and improved glucose tolerance and insulin sensitivity. Furthermore, PER treatment also decreased lipid contents in liver, brown adipose tissue, and white adipose tissue. Our results from the present study suggested that petroleum ether fraction of rosemary extracts exhibited the best potential of improving lipid metabolism by inhibiting SREBPs activity.
文摘目的:探讨固醇调节元件结合蛋白(sterol regulatory elementbinding proteins,SREBPs)与冠心病的相关性。方法:选择冠心病患者65例及正常对照55例,利用RT-qPCR方法检测外周血白细胞SREBP1及SREBP2相对表达量;利用全自动生化分析仪检测血糖血脂等生化项目;使用受试者工作特征(receiver operating characteristic,ROC)曲线和曲线下面积(area under the curve,AUC)分析SREBPs对冠心病诊断的敏感度和特异度。结果:与对照组相比,冠心病组SREBP1及SREBP2相对表达量均显著下降,差异有统计学意义(P<0.001);SREBPs的ROC结果显示,SREBP1的AUC值为0.710,SREBP2的AUC值为0.697。结论:静脉血白细胞中SREBPs下调可能预示冠心病的发生。推测SREBPs可能成为冠心病早期诊断的一个潜在的生物标志物。
基金financial support of the National Natural Science Foundation of China(82370532,82341219)Shanghai Hospital Development Center Foundation(SHDC12022118)。
文摘YdjC chitooligosaccharide deacetylase homolog(YDJC)has been identified as a susceptibility gene for inflammatory bowel disease(IBD),yet its role in the pathogenesis of IBD,particularly in regulating immune responses in the gut mucosa,remains elusive.In this study,we demonstrated that YDJC expression is downregulated in inflamed mucosa,particularly in the CD4^(+)T cells of IBD patients,and that Ydjc deficiency promotes CD4^(+)T-cell proliferation and Th1 cell differentiation,thereby exacerbating acute and chronic colitis in mice.Integrative transcriptomic,proteomic,and metabolomic analyses revealed that Ydjc^(-/-)CD4^(+)T cells exhibit upregulated SREBP2-mediated cholesterol biosynthesis.Consistently,treatment with key enzyme inhibitors targeting cholesterol biosynthesis,including simvastatin,fatostatin,and AAV-sh-Srebf2,markedly suppressed CD4^(+)T-cell proliferation and Th1 cell differentiation,thereby alleviating colitis in Ydjc^(-/-)mice.Mechanistically,YDJC directly deacetylates SREBP2,which further suppresses downstream target gene expression(e.g.,Hmgcr,Hmgcs1,and Cyp51).Therefore,our findings elucidate a novel mechanism whereby YDJC restrains intestinal mucosal inflammation by downregulating SREBP2-driven Th1 cell differentiation,suggesting that targeting YDJC and SREBP2-mediated cholesterol biosynthesis may serve as promising therapeutic strategies for IBD.
文摘Sterol regulator element binding proteins(SREBPs)are a family of transcription factors involved in the biogenesis of cholesterol,fatty acids and triglycerides.They also regulate physiological functions of many organs,such as thyroid,brain,heart,pancreas and hormone synthesis.Beside the physiological effects,SREBPs participate in some pathological processes,diabetes,endoplasmic reticulum stress,atherosclerosis and chronic kidney disease associated with SREBP expression changes.In the liver,SREBPs are involved in the pathogenesis of nonalcoholic fatty liver disease,nonalcoholic steatohepatitis,hepatitis and hepatic cancer.There are several SREBP inhibitors that have potential for treating obesity,diabetes and cancer.This review assesses the recent findings about the roles of SREBPs in the physiology of organs'function and pathogenesis of liver diseases.
基金financial support from the National Natural Science Foundation of China(81922072 and 81973443)“Double First-Class”University project(CPU2018PZQ16 and CPU2018GF04,China)+2 种基金the Project of State Key Laboratory of Natural Medicines(SKLNMZZ202006,China)the Open Project of State Key Laboratory of Natural Medicines(SKLNMKF202010,China)a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(China)。
文摘The mammalian target of rapamycin(mTOR)-sterol regulatory element-binding proteins(SREBPs)signaling promotes lipogenesis.However,mTOR inhibitors also displayed a significant side effect of hyperlipidemia.Thus,it is essential to develop mTOR-specific inhibitors to inhibit lipogenesis.Here,we screened the endogenous inhibitors of mTOR,and identified that FKBP38 as a vital regulator of lipid metabolism.FKBP38 decreased the lipid content in vitro and in vivo via suppression of the mTOR/P70 S6 K/SREBPs pathway.3,5,6,7,8,3’,4’-Heptamethoxyflavone(HMF),a citrus flavonoid,was found to target FKBP38 to suppress the mTOR/P70 S6 K/SREBPs pathway,reduce lipid level,and potently ameliorate hyperlipidemia and insulin resistance in high fat diet(HFD)-fed mice.Our findings suggest that pharmacological intervention by targeting FKBP38 to suppress mTOR/P70 S6 K/SREBPs pathway is a potential therapeutic strategy for hyperlipidemia,and HMF could be a leading compound for development of anti-hyperlipidemia drugs.
文摘目的探讨前列腺癌组织中固醇调节元件结合蛋白1(SREBP1)、乙酰辅酶A羧化酶α(ACCα)的表达及对前列腺癌细胞系DU145增殖、迁移和侵袭的影响。方法通过在线网站TIMER、UALCAN、GEPIA和THE HUMAN PROTEIN ATLAS分析SREBP1和ACCα在前列腺癌中表达情况。收集合肥医科大学第五附属(珠海)医院2016年1月至2018年12月期间收治的58例前列腺癌(PCa)和58例良性前列腺增生(BPH)患者石蜡标本,采用免疫组织化学法检测上述组织中SREBP1和ACCα的表达;采用shRNA下调DU145细胞中SREBP1的表达后,qRT-PCR检测ACCα的表达变化;采用CCK-8法检测细胞增殖能力;流式细胞仪检测细胞周期分布;Western blot实验检测SREBP1和ACCα的表达;通过Transwell迁移和侵袭实验检测沉默SREBP1后DU145细胞迁移和侵袭的变化;细胞划痕愈合实验检测干扰SREBP1后对DU145细胞划痕愈合能力的影响;EdU实验检测沉默SREBP1表达后细胞增殖能力;通过油红O染色,观察干扰SREBP1的表达后,前列腺癌细胞中脂质含量变化。结果TIMER、UALCAN在线数据库分析发现,同正常前列腺组织相比,ACCα在前列腺癌中表达显著升高(P<0.001)。沉默SREBP1后,DU145细胞增殖、迁移和侵袭能力均较对照组显著降低(P<0.01);流式细胞术检测沉默SREBP1后DU145细胞发生G1期阻滞(P<0.01)。SREBP1敲低后前列腺癌细胞中脂肪含量显著降低(P<0.01)。结论SREBP1可能通过调控ACCα的表达,促进前列腺癌细胞增殖、迁移和侵袭。
