Acute liver failure(ALF)is a medical emergency due to massive hepatocyte loss.In such a harsh condition,maintaining transcriptional regulation in the remaining hepatocytes while activating similar transcription factor...Acute liver failure(ALF)is a medical emergency due to massive hepatocyte loss.In such a harsh condition,maintaining transcriptional regulation in the remaining hepatocytes while activating similar transcription factor networks in liver progenitor cells(LPCs)to ensure essential liver functions are two critical processes to rescue patients from liver failure and death.In this review,we discuss the formation and functions of transcription networks in ALF and liver development.We focus on a hierarchical network of transcription factors that responds to different pathophysiological circumstances:(1)Under normal circumstances,pioneer factor forkhead box protein A2(FOXA2)coordinates several constitutive hepatic transcription factors,such as hepatic nuclear factor 4 alpha(HNF4a)and CCAAT-enhancer binding protein a(C/EBPa),which ensure normal liver function;(2)When the expression of both HNF4a and C/EBPa in hepatocytes are disrupted by severe inflammation,retinoic acid receptor(RAR)is the alternative transcription factor that compensates for their absence;(3)When massive hepatic necrosis occurs,a similar transcription network including FOXA2 and HNF4a,is activated as a“rescue network”in LPCs to maintain vital liver functions when hepatocytes fail,and thus ensures survival.Expression of these master transcription factors in hepatocytes and LPCs is tightly regulated by hormone signals and inflammation.The performance of this hierarchical transcription network,in particularly the“rescue network”described above,significantly affects the clinical outcome of ALF.展开更多
基金supported by the Deutsche For-schungsge meinschaft WE 5009/9e1,Chinese-German Cooperation Group projects GZ 1517(H.-L.Weng)BMBF through HiChol 01GM1904A(R.Liebe).R.Feng is supported by the Chinese Scholarship Council(Grant No.201706230256).
文摘Acute liver failure(ALF)is a medical emergency due to massive hepatocyte loss.In such a harsh condition,maintaining transcriptional regulation in the remaining hepatocytes while activating similar transcription factor networks in liver progenitor cells(LPCs)to ensure essential liver functions are two critical processes to rescue patients from liver failure and death.In this review,we discuss the formation and functions of transcription networks in ALF and liver development.We focus on a hierarchical network of transcription factors that responds to different pathophysiological circumstances:(1)Under normal circumstances,pioneer factor forkhead box protein A2(FOXA2)coordinates several constitutive hepatic transcription factors,such as hepatic nuclear factor 4 alpha(HNF4a)and CCAAT-enhancer binding protein a(C/EBPa),which ensure normal liver function;(2)When the expression of both HNF4a and C/EBPa in hepatocytes are disrupted by severe inflammation,retinoic acid receptor(RAR)is the alternative transcription factor that compensates for their absence;(3)When massive hepatic necrosis occurs,a similar transcription network including FOXA2 and HNF4a,is activated as a“rescue network”in LPCs to maintain vital liver functions when hepatocytes fail,and thus ensures survival.Expression of these master transcription factors in hepatocytes and LPCs is tightly regulated by hormone signals and inflammation.The performance of this hierarchical transcription network,in particularly the“rescue network”described above,significantly affects the clinical outcome of ALF.
