代谢相关性脂肪肝病(MAFLD)是一种正在全球范围流行的慢性肝病,曾用名非酒精性脂肪肝病(NAFLD)。肝纤维化是MAFLD病情进展中的重要阶段,随着肝纤维化的发展有极大风险进展为肝硬化、肝癌。对MAFLD患者进行肝纤维化评估可以达到早期干预...代谢相关性脂肪肝病(MAFLD)是一种正在全球范围流行的慢性肝病,曾用名非酒精性脂肪肝病(NAFLD)。肝纤维化是MAFLD病情进展中的重要阶段,随着肝纤维化的发展有极大风险进展为肝硬化、肝癌。对MAFLD患者进行肝纤维化评估可以达到早期干预和改善预后的目的,剪切波弹性成像(SWE)是一种肝纤维化诊断的非侵入性技术,以其简便、快捷、高效的检查特点在临床得到了广泛的应用。本文旨在对当前SWE在MAFLD肝纤维化诊断中的应用进展进行综述。Metabolic-associated fatty liver disease (MAFLD) is a chronic liver disease that is becoming endemic worldwide, formerly known as non-alcoholic fatty liver disease (NAFLD). Liver fibrosis is an important stage in the progression of MAFLD, and with the development of liver fibrosis, there is a great risk of progression to liver cirrhosis and liver cancer. Shear wave elastography (SWE) is a non-invasive technique for the diagnosis of liver fibrosis, which has been widely used in clinical practice due to its simple, fast and efficient examination characteristics. This article is to review the current progress in the application of SWE in the diagnosis of liver fibrosis in MAFLD.展开更多
Background and aims:Metabolic dysfunction-associated fatty liver disease(MAFLD)is a common chronic condition that can lead to cancer due to its complex pathogenesis.Therapeutic agents targeting AMPactivated protein ki...Background and aims:Metabolic dysfunction-associated fatty liver disease(MAFLD)is a common chronic condition that can lead to cancer due to its complex pathogenesis.Therapeutic agents targeting AMPactivated protein kinase(AMPK)activation have been suggested as potential treatments for metabolic disorders such as metabolic dysfunction-associated steatohepatitis(MASH).Rhizoma Atractylodis Macrocephalae(RAM)has been clinically used to treat obesity-related health problems,but its therapeutic effects on MAFLD and the underlying mechanism remain unclear.Therefore,this study was conducted to evaluate the function and underlying mechanism of RAM in the treatment of MAFLD.Methods:The effect of RAM decoction on MAFLD was evaluated using a high-fat diet(HFD)-induced MAFLD mouse model.In vitro studies were conducted using a palmitic acid/oleic acid-induced lipid accumulation model in the alpha mouse liver 12 cells and RAM-containing serum.The underlying mechanisms were elucidated through a combination of network pharmacology analysis,immunohistochemistry,western blotting,and polymerase chain reaction analysis.Results:Administration of RAM decoction significantly reduced body weight gain in MAFLD mice without changing food intake.The weights of the liver and inguinal adipose tissues were also reduced after RAM treatment.Additionally,RAM administration decreased serum levels of alanine aminotransferase,aspartate transaminase,total cholesterol,triglyceride,low-density lipoprotein cholesterol,and glucose,while reducing lipid droplet accumulation in the liver tissues of MAFLD mice.The underlying mechanisms included the activation of the phosphorylation of AMPK and acetyl-CoA carboxylase(ACC),and inhibition of the expression of sterol regulatory element binding protein 1(SREBP1).However,RAM did not alter the protein expression levels of peroxisome proliferator-activated receptor a and carnitine palmitoyltransferase-1a.Furthermore,the RAM-induced upregulation of phosphorylated AMPK,phosphorylated ACC,and SREBP1 expression,as well as the downregulation of fatty acid synthase expression,were reversed by using an AMPK inhibitor.Conclusions:Through a combination of network pharmacology and experimental validation,we demonstrated that RAM may exert therapeutic effects on MAFLD by inhibiting lipid synthesis and activating phosphorylated AMPK pathways.展开更多
Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease(MAFLD).However,there are few reported lipotoxicity inhibitors...Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease(MAFLD).However,there are few reported lipotoxicity inhibitors.Here,we identified a natural anti-lipotoxicity candidate,HN-001,from the marine fungus Aspergillus sp.C1.HN-001 dose-and time-dependently reversed palmitic acid(PA)-induced hepatocyte death.This protection was associated with IRE-1a-mediated XBP-1 splicing inhibition,which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation.Knockdown of XBP-1s attenuated lipotoxicity,but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes.Notably,the ER stress and lipotoxicity amelioration was associated with PLA2.Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity,reduced lysophosphatidylcholine(LPC)level,subsequently ameliorated lipotoxicity.In contrast,overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001.Additionally,HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway.In vivo,chronic administration of HN-001(i.p.)in mice alleviated all manifestations of MAFLD,including hepatic steatosis,liver injury,inflammation,and fibrogenesis.These effects were correlated with PLA2/IRE-1a/XBP-1s axis and JNK signaling suppression.These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity,and provide a natural structural basis for developing anti-MAFLD candidates.展开更多
Fatty liver disease is a commonly occurring disease resulting in hepatic and extrahepatic complications.To date,there have been few available treatments beyond conventional lifestyle modification.While lifestyle modif...Fatty liver disease is a commonly occurring disease resulting in hepatic and extrahepatic complications.To date,there have been few available treatments beyond conventional lifestyle modification.While lifestyle modifications resulting in weight loss>10%have shown to be beneficial for metabolic dysfunction-associated steatohepatitis(MASH),for the majority of patients,this is difficult to achieve.The recent approval of resmetirom(a thyroid hormone receptor beta agonist)by the Food and Drug Administration following positive results for histological outcomes in a phase 3 trial has opened the door for new treatments for metabolic(dysfunction)-associated fatty liver disease(MAFLD)and MASH.There are currently a number of phase 3 trials targeting a variety of signaling pathways involved in the pathogenesis of metabolic steatohepatitis that are also promising.This review focuses on the currently available treatments for MAFLD and MASH,ongoing phase 3 clinical trials,and unresolved controversies in clinical trials in this area.展开更多
目的:通过网络药理学探索中药荷叶治疗代谢相关脂肪性肝病(metabolic dysfunction associated fatty liver disease,MAFLD)的潜在作用机制并进行验证。方法:使用中药系统数据库及分析平台(traditional Chinese medicine systems pharmac...目的:通过网络药理学探索中药荷叶治疗代谢相关脂肪性肝病(metabolic dysfunction associated fatty liver disease,MAFLD)的潜在作用机制并进行验证。方法:使用中药系统数据库及分析平台(traditional Chinese medicine systems pharmacology database and analysis platform,TCMSP)、Uniprot数据库搜集和匹配中药荷叶的活性成分和相应靶点,采用人类基因综合数据库(GeneCards)、人类孟德尔遗传(online Mendelian inheritance in man,OMIM)数据库预测MAFLD靶点基因,利用在线交集工具(Venny 2.1)获取药物与疾病的交集靶点;使用String数据库构建蛋白质相互作用关系网络,导出文件后在软件(Cytoscape 3.7.2)中输出核心靶点和构建“中药成分-靶点-疾病”可视化网络图;将核心靶点进行基因本体论(gene ontology,GO)及京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)功能和通路的富集分析;使用国家生物技术信息中心(national center of biotechnology information,NCBI)数据库中基因表达矩阵数据进行核心基因的差异分析及回归曲线分析验证,根据受试者工作特征曲线(receiver operating characteristic,ROC)结果筛选差异显著的基因进行分子对接以评估成分与靶点基因的稳定性;同时,通过成分干预人肝癌细胞株G2型(hepatocellular carcinomas G2,HepG2)细胞脂肪变性模型后测定相关蛋白的表达水平。结果:共获得中药荷叶活性成分14个,包括槲皮素、儿茶酸、异鼠李亭等;成分所对应的靶点有177个,疾病对应的靶点有274个,“药物-疾病”交集靶点9个;核心靶点在String数据库中的蛋白相互作用表明荷叶成分可能作用于白细胞介素-6(interleukin-6,IL6)、白细胞介素-10(interleukin-10,IL10)、表皮生长因子受体(epidermal growth factor receptor,EGFR)、热休克蛋白-β1(heat shock protein beta-1,HSPB1)、中性粒细胞胞浆因子1(neutrophil cytosolic factor 1,NCF1)、过氧化物酶体增殖物激活受体α(peroxisome proliferator-activated receptorα,PPARA)、过氧化物酶体激活物受体δ(peroxisome proliferator activated receptorδ,PPARD)、血清对氧磷酶(para⁃oxonase,PON1)、脂肪酸合成酶(fatty acid synthase,FASN)等多个靶点;基因的信号通路分析表明,核心基因可能参与调控FoxO、酪氨酸激酶-信号传导子及转录激活子(Janus tyrosine kinase-signal transducer and activator of transcription,JAK-STAT)、过氧化物酶体增殖物激活受体(peroxisome proliferators activated receptors,PPAR)、基因组丝氨酸和苏氨酸的蛋白激酶(mitogen-activated protein kinase,MAPK)、肠道炎症等相关信号通路;基因表达数据分析表明在对照组与实验组中最具有显著性的基因是IL6、IL10、FASN、PPARA等,其中只有IL6和IL10的曲线下面积(area under the curve,AUC)在90%以上;通过分子对接分析得到成分槲皮素与IL6和IL10的稳定性较好;细胞实验结果显示不同浓度的槲皮素在干预HepG2细胞脂肪变性模型后,蛋白IL6的表达水平呈浓度依赖性降低。结论:中药荷叶治疗MAFLD的炎症及脂质沉积,其机制可能与槲皮素调控IL6、IL10等蛋白表达有关。展开更多
文章对以中医运动处方为主,治疗代谢相关(非酒精性)脂肪性肝病(MAFLD)的方法和疗效进行综述;并分析当前以中医运动处方为手段干预MAFLD的治疗模式中存在的主要问题。The article provides a review of the methods and efficacy of usin...文章对以中医运动处方为主,治疗代谢相关(非酒精性)脂肪性肝病(MAFLD)的方法和疗效进行综述;并分析当前以中医运动处方为手段干预MAFLD的治疗模式中存在的主要问题。The article provides a review of the methods and efficacy of using traditional Chinese medicine exercise prescriptions to treat metabolic related (non-alcoholic) fatty liver disease (MAFLD);And analyze the main problems in the current treatment mode of using traditional Chinese medicine exercise prescription as a means to intervene in MAFLD.展开更多
To provide clarity for research studies and clinical care,a set of positive criteria for adults and children with metabolic(dysfunction)associated fatty liver disease(MAFLD)was recently published and has subsequently ...To provide clarity for research studies and clinical care,a set of positive criteria for adults and children with metabolic(dysfunction)associated fatty liver disease(MAFLD)was recently published and has subsequently been widely endorsed.The development and subsequent validation of the criteria for MAFLD has created a positive momentum for change.During the course of the ongoing discussion on the redefinition,some concerns have surfaced that we thought needs clarification.In this review,we provide a perspective on MAFLD and bringing clarity to some of the key aspects that have been recently raised.展开更多
文摘代谢相关性脂肪肝病(MAFLD)是一种正在全球范围流行的慢性肝病,曾用名非酒精性脂肪肝病(NAFLD)。肝纤维化是MAFLD病情进展中的重要阶段,随着肝纤维化的发展有极大风险进展为肝硬化、肝癌。对MAFLD患者进行肝纤维化评估可以达到早期干预和改善预后的目的,剪切波弹性成像(SWE)是一种肝纤维化诊断的非侵入性技术,以其简便、快捷、高效的检查特点在临床得到了广泛的应用。本文旨在对当前SWE在MAFLD肝纤维化诊断中的应用进展进行综述。Metabolic-associated fatty liver disease (MAFLD) is a chronic liver disease that is becoming endemic worldwide, formerly known as non-alcoholic fatty liver disease (NAFLD). Liver fibrosis is an important stage in the progression of MAFLD, and with the development of liver fibrosis, there is a great risk of progression to liver cirrhosis and liver cancer. Shear wave elastography (SWE) is a non-invasive technique for the diagnosis of liver fibrosis, which has been widely used in clinical practice due to its simple, fast and efficient examination characteristics. This article is to review the current progress in the application of SWE in the diagnosis of liver fibrosis in MAFLD.
基金supported by the National Natural Science Foundation of China(No.82370582 to Xiaoni Kong)The YangFan project from the Science and Technology Commission of Shanghai Municipality(No.22YF1449600 to Jiacheng Lin)State Administration of Traditional Chinese Medicine High-level Key Disciplines Program(No.ZYYZDXK-2023060)。
文摘Background and aims:Metabolic dysfunction-associated fatty liver disease(MAFLD)is a common chronic condition that can lead to cancer due to its complex pathogenesis.Therapeutic agents targeting AMPactivated protein kinase(AMPK)activation have been suggested as potential treatments for metabolic disorders such as metabolic dysfunction-associated steatohepatitis(MASH).Rhizoma Atractylodis Macrocephalae(RAM)has been clinically used to treat obesity-related health problems,but its therapeutic effects on MAFLD and the underlying mechanism remain unclear.Therefore,this study was conducted to evaluate the function and underlying mechanism of RAM in the treatment of MAFLD.Methods:The effect of RAM decoction on MAFLD was evaluated using a high-fat diet(HFD)-induced MAFLD mouse model.In vitro studies were conducted using a palmitic acid/oleic acid-induced lipid accumulation model in the alpha mouse liver 12 cells and RAM-containing serum.The underlying mechanisms were elucidated through a combination of network pharmacology analysis,immunohistochemistry,western blotting,and polymerase chain reaction analysis.Results:Administration of RAM decoction significantly reduced body weight gain in MAFLD mice without changing food intake.The weights of the liver and inguinal adipose tissues were also reduced after RAM treatment.Additionally,RAM administration decreased serum levels of alanine aminotransferase,aspartate transaminase,total cholesterol,triglyceride,low-density lipoprotein cholesterol,and glucose,while reducing lipid droplet accumulation in the liver tissues of MAFLD mice.The underlying mechanisms included the activation of the phosphorylation of AMPK and acetyl-CoA carboxylase(ACC),and inhibition of the expression of sterol regulatory element binding protein 1(SREBP1).However,RAM did not alter the protein expression levels of peroxisome proliferator-activated receptor a and carnitine palmitoyltransferase-1a.Furthermore,the RAM-induced upregulation of phosphorylated AMPK,phosphorylated ACC,and SREBP1 expression,as well as the downregulation of fatty acid synthase expression,were reversed by using an AMPK inhibitor.Conclusions:Through a combination of network pharmacology and experimental validation,we demonstrated that RAM may exert therapeutic effects on MAFLD by inhibiting lipid synthesis and activating phosphorylated AMPK pathways.
基金This study was supported by National Natural Science Foundation of China(82260674 to Yong Rao,82160653 to Ling Huang)Fundamental Research Funds for Hainan University(KYQD(ZR)-21114 to Yong Rao,KYQD(ZR)-21089 to Ling Huang,China)+2 种基金Hainan Provincial Natural Science Foundation of China(822MS054 to Yong Rao)Natural Science Foundation of Guangdong Province(2021A1515010488 to Yong Rao,China)Central Public-interest Scientific Institution Basal Research Fund for CATAS-ITBB(1630052022016,1630052019011,China).
文摘Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease(MAFLD).However,there are few reported lipotoxicity inhibitors.Here,we identified a natural anti-lipotoxicity candidate,HN-001,from the marine fungus Aspergillus sp.C1.HN-001 dose-and time-dependently reversed palmitic acid(PA)-induced hepatocyte death.This protection was associated with IRE-1a-mediated XBP-1 splicing inhibition,which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation.Knockdown of XBP-1s attenuated lipotoxicity,but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes.Notably,the ER stress and lipotoxicity amelioration was associated with PLA2.Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity,reduced lysophosphatidylcholine(LPC)level,subsequently ameliorated lipotoxicity.In contrast,overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001.Additionally,HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway.In vivo,chronic administration of HN-001(i.p.)in mice alleviated all manifestations of MAFLD,including hepatic steatosis,liver injury,inflammation,and fibrogenesis.These effects were correlated with PLA2/IRE-1a/XBP-1s axis and JNK signaling suppression.These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity,and provide a natural structural basis for developing anti-MAFLD candidates.
基金Robert W.Storr Bequest to the Sydney Medical Foundation,University of SydneyNational Health and Medical Research Council of Australia(NHMRC)Program,Grant/Award Number:APP1053206+1 种基金Investigator and MRFF,Grant/Award Numbers:APP2032407,NCRI000183,APP2016215,APP2010795,APP1196492Cancer Institute,NSW,Grant/Award Number:2021/ATRG2028。
文摘Fatty liver disease is a commonly occurring disease resulting in hepatic and extrahepatic complications.To date,there have been few available treatments beyond conventional lifestyle modification.While lifestyle modifications resulting in weight loss>10%have shown to be beneficial for metabolic dysfunction-associated steatohepatitis(MASH),for the majority of patients,this is difficult to achieve.The recent approval of resmetirom(a thyroid hormone receptor beta agonist)by the Food and Drug Administration following positive results for histological outcomes in a phase 3 trial has opened the door for new treatments for metabolic(dysfunction)-associated fatty liver disease(MAFLD)and MASH.There are currently a number of phase 3 trials targeting a variety of signaling pathways involved in the pathogenesis of metabolic steatohepatitis that are also promising.This review focuses on the currently available treatments for MAFLD and MASH,ongoing phase 3 clinical trials,and unresolved controversies in clinical trials in this area.
文摘目的:通过网络药理学探索中药荷叶治疗代谢相关脂肪性肝病(metabolic dysfunction associated fatty liver disease,MAFLD)的潜在作用机制并进行验证。方法:使用中药系统数据库及分析平台(traditional Chinese medicine systems pharmacology database and analysis platform,TCMSP)、Uniprot数据库搜集和匹配中药荷叶的活性成分和相应靶点,采用人类基因综合数据库(GeneCards)、人类孟德尔遗传(online Mendelian inheritance in man,OMIM)数据库预测MAFLD靶点基因,利用在线交集工具(Venny 2.1)获取药物与疾病的交集靶点;使用String数据库构建蛋白质相互作用关系网络,导出文件后在软件(Cytoscape 3.7.2)中输出核心靶点和构建“中药成分-靶点-疾病”可视化网络图;将核心靶点进行基因本体论(gene ontology,GO)及京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)功能和通路的富集分析;使用国家生物技术信息中心(national center of biotechnology information,NCBI)数据库中基因表达矩阵数据进行核心基因的差异分析及回归曲线分析验证,根据受试者工作特征曲线(receiver operating characteristic,ROC)结果筛选差异显著的基因进行分子对接以评估成分与靶点基因的稳定性;同时,通过成分干预人肝癌细胞株G2型(hepatocellular carcinomas G2,HepG2)细胞脂肪变性模型后测定相关蛋白的表达水平。结果:共获得中药荷叶活性成分14个,包括槲皮素、儿茶酸、异鼠李亭等;成分所对应的靶点有177个,疾病对应的靶点有274个,“药物-疾病”交集靶点9个;核心靶点在String数据库中的蛋白相互作用表明荷叶成分可能作用于白细胞介素-6(interleukin-6,IL6)、白细胞介素-10(interleukin-10,IL10)、表皮生长因子受体(epidermal growth factor receptor,EGFR)、热休克蛋白-β1(heat shock protein beta-1,HSPB1)、中性粒细胞胞浆因子1(neutrophil cytosolic factor 1,NCF1)、过氧化物酶体增殖物激活受体α(peroxisome proliferator-activated receptorα,PPARA)、过氧化物酶体激活物受体δ(peroxisome proliferator activated receptorδ,PPARD)、血清对氧磷酶(para⁃oxonase,PON1)、脂肪酸合成酶(fatty acid synthase,FASN)等多个靶点;基因的信号通路分析表明,核心基因可能参与调控FoxO、酪氨酸激酶-信号传导子及转录激活子(Janus tyrosine kinase-signal transducer and activator of transcription,JAK-STAT)、过氧化物酶体增殖物激活受体(peroxisome proliferators activated receptors,PPAR)、基因组丝氨酸和苏氨酸的蛋白激酶(mitogen-activated protein kinase,MAPK)、肠道炎症等相关信号通路;基因表达数据分析表明在对照组与实验组中最具有显著性的基因是IL6、IL10、FASN、PPARA等,其中只有IL6和IL10的曲线下面积(area under the curve,AUC)在90%以上;通过分子对接分析得到成分槲皮素与IL6和IL10的稳定性较好;细胞实验结果显示不同浓度的槲皮素在干预HepG2细胞脂肪变性模型后,蛋白IL6的表达水平呈浓度依赖性降低。结论:中药荷叶治疗MAFLD的炎症及脂质沉积,其机制可能与槲皮素调控IL6、IL10等蛋白表达有关。
文摘文章对以中医运动处方为主,治疗代谢相关(非酒精性)脂肪性肝病(MAFLD)的方法和疗效进行综述;并分析当前以中医运动处方为手段干预MAFLD的治疗模式中存在的主要问题。The article provides a review of the methods and efficacy of using traditional Chinese medicine exercise prescriptions to treat metabolic related (non-alcoholic) fatty liver disease (MAFLD);And analyze the main problems in the current treatment mode of using traditional Chinese medicine exercise prescription as a means to intervene in MAFLD.
基金supported by the Robert W.Storr Bequest to the Sydney Medical Foundation,University of Sydneya National Health and Medical Research Council of Australia(NHMRC)Program and investigator grants(APP2008983 and APP1053206)project and idea grants(APP2001692,APP1107178 and APP1108422).
文摘To provide clarity for research studies and clinical care,a set of positive criteria for adults and children with metabolic(dysfunction)associated fatty liver disease(MAFLD)was recently published and has subsequently been widely endorsed.The development and subsequent validation of the criteria for MAFLD has created a positive momentum for change.During the course of the ongoing discussion on the redefinition,some concerns have surfaced that we thought needs clarification.In this review,we provide a perspective on MAFLD and bringing clarity to some of the key aspects that have been recently raised.
