Runt-related transcription factor-1 ameliorates bile acid–induced hepatic inflammation in cholestasis through JAK/STAT3 signaling

Abstract

Background and Aims: Bile acids trigger a hepatic inflammatory response, causing cholestatic liver injury. Runt-related transcription factor-1 (RUNX1), primarily known as a master modulator in hematopoiesis, plays a pivotal role in mediating inflammatory responses. However, RUNX1 in hepatocytes is poorly characterized, and its role in cholestasis is unclear. Herein, we aimed to investigate the role of hepatic RUNX1 and its underlying mechanisms in cholestasis. Approach and Results: Hepatic expression of RUNX1 was examined in cholestatic patients and mouse models. Mice with liver-specific ablation of Runx1 were generated. Bile duct ligation and 1% cholic acid diet were used to induce cholestasis in mice. Primary mouse hepatocytes and the human hepatoma PLC/RPF/5-ASBT cell line were used for mechanistic studies. Hepatic RUNX1 mRNA and protein levels were markedly increased in cholestatic patients and mice. Liver-specific deletion of Runx1 aggravated inflammation and liver injury in cholestatic mice induced by bile duct ligation or 1% cholic acid feeding. Mechanistic studies indicated that elevated bile acids stimulated RUNX1 expression by activating the RUNX1-P2 promoter through JAK/STAT3 signaling. Increased RUNX1 is directly bound to the promotor region of inflammatory chemokines, including CCL2 and CXCL2, and transcriptionally repressed their expression in hepatocytes, leading to attenuation of liver inflammatory response. Blocking the JAK signaling or STAT3 phosphorylation completely abolished RUNX1 repression of bile acid–induced CCL2 and CXCL2 in hepatocytes. Conclusions: This study has gained initial evidence establishing the functional role of hepatocyte RUNX1 in alleviating liver inflammation during cholestasis through JAK/STAT3 signaling. Modulating hepatic RUNX1 activity could be a new therapeutic target for cholestasis.

Pioneer Factor Foxa2 Mediates Chromatin Conformation Changes for Activation of Bile Acid Targets of FXR

“… 21 We also used published ChIP-Seq data sets in the mouse genome and intersected differential TAD regions and the binding data present in the ChEA database, identifying overlap with RUNX1, TP53, β-catenin, and LXR targets ( Figure 5 B , bottom , ChEA analysis in Enrich). RUNX1 improves bile–acid induced hepatic inflammation in cholestasis, 22 p53 plays a role in bile acid metabolism by regulating SHP ( Nr0b2 ), 23 and β-catenin regulates FXR-dependent gene expression in cholestasis. 24 Hence our analysis of differential TADs identified regulators important for bile acid homeostasis and shows that ligand-dependent activation of FXR is associated with substantial changes in TAD distribution.…”

“…We have identified several regulators of genes in differential interactions and TAD regions, including NRF2 ( Nfe2l2 ), glucocorticoid receptor (GR, NR3C1), Runx1, and β-catenin. Most factors are protective in cholestasis 22 , 24 , 25 (β-catenin, NRF2, Runx1), whereas glucocorticoids promote the disease. 26 However, activation of gene expression by these regulators has implications for other disorders, primarily metabolic dysfunction–associated steatotic liver disease (formerly nonalcoholic fatty liver disease) and hepatocellular carcinoma.…”

Pioneer factor Foxa2 mediates chromatin conformation changes in ligand-dependent activation of nuclear receptor FXR

“…3b, bottom panel, ChEA analysis in Enrich). RUNX1 improves bile-acid induced hepatic inflammation in cholestasis 14 , p53 plays a role in bile acid metabolism by regulating SHP ( Nr0b2 ) 15 , and β-catenin regulates FXR-dependent gene expression in cholestasis 16 . Hence our analysis of differential TADs identified regulators important for bile acid homeostasis and shows that ligand-dependent activation of FXR is associated with substantial changes in TAD distribution.…”

SHP-1 interacts with NFκB1 to inhibit its phosphorylation and nuclear translocation to suppress excessive bacterial inflammation

“…Going beyond the phenotypic observations, we investigated the molecular mechanisms underlying SHP-1’s immunomodulatory effects. After pathogen infections, immune-related signaling pathways including TLR5-MYD88-NFκB and JAK-STAT3 were activated, leading to the production and release of pro-inflammatory cytokines, including IL-1β and IL-6 ( 12, 13, 16, 18 ). The exaggerated activation of these signaling cascades and excessive release of inflammatory cytokines is the central mechanism that initiates cytokine storm, damage to tissues and organs, and even death ( 15, 21 ).…”