A hierarchical regulatory network ensures stable albumin transcription under various pathophysiological conditions

Physiologically, albumin is produced by hepatocytes. It remains largely unknown how patients are capable of maintaining essential albumin levels even in the condition of liver failure. Here, we delineate a hierarchical regulatory network that controls albumin transcription under different pathophysiological conditions. The ALB core promoter possesses a TATA box and nucleosome-free area, which allows constitutive binding of RNA Pol II and thus initiation of transcription. In normal conditions, HNF4a and C/EBPa facilitate albumin transcription through binding to its promoter. In severely damaged livers, hepatocellular HNF4a and C/EBPa expression is often inhibited. The absence of HNF4? and C/EBPa increases hedgehog ligand biosynthesis. Hedgehog upregulates FOXA2 expression through transcription factor GLI2 binding to the FOXA2 promoter. Subsequently, FOXA2 maintains albumin expression in the hepatocytes lacking HNF4a and C/EBPa. In patients with massive hepatocyte loss, the expression of albumin is activated in liver progenitor cells. Albumin transcription in these cells is regulated by HNF4a or FOXA2. Taken together, HNF4a, C/EBPa and FOXA2 form a hierarchical regulatory network that ensures stable albumin expression even in pathophysiological conditions. Overall design: Mouse primary hepatocytes (MPH) were freshly isolated from three mice: Mouse1, Mouse2, Mouse3. RNA sequencing was performed in MPH with or without HNF4a and C/EBPa siRNA treatment for 48 hours.