Work

Alcohol-related hepatitis induces a specific fibrosis profile through YAP activation in myofibroblasts

Year: 2025

Type: article

Abstract: Background & Aims YAP impairs hepatocyte regeneration in alcohol-related hepatitis (AH), but its impact on fibrogenesis remains to be characterized. Our aim was to describe fibrogenesis and investigate the impact of altered hepatocytes on fibrogenic mechanisms during AH. Methods Fibrosis, YAP and αSMA distribution were assessed by immunostaining. Extracellular matrix (ECM) composition in severe AH (n=22), alcohol-related cirrhosis (Cirrh, n=24) and healthy livers (CTRL, n=15) was assessed by PCR, bulk and spatial proteomics. The impact of organoids generated from AH and Cirrh livers on myofibroblasts was evaluated. Cirrh organoids were transduced with constitutively active YAP (to mimic AH organoids) and cocultured with myofibroblasts in a 3D-coculture model. In a 2D model, myofibroblasts were treated with GDF 15 or cultured with medium from transduced (YAP medium) and non-transduced hepatocytes. Results AH livers presented with both perilobular (as in Cirrh livers) and specifically intralobular fibrosis. Bulk proteomics and PCR showed a specific ECM protein signature (e.g. laminin A2 was increased (p<0.05) while vitronectin was decreased (p<0.001) in AH. Spatial proteomics showed differences in ECM composition between intralobular and perilobular areas in AH and Cirrh livers. AH organoids overexpressed YAP(p<0.01). In the 3D model, AH organoids induced greater activation (e.g. αSMA mRNA level increased by 3-fold, p<0.001) of cocultured myofibroblasts. YAP-transduced Cirrh organoids also induced greater activation of cocultured myofibroblasts: αSMA mRNA level increased by 1.5-fold, p<0.05. In the 2D model, YAP medium also induced increased myofibroblast activation (αSMA mRNA level increased by 1.5-fold, p<0.01) and proliferation (23% increase, p<0.05) in part through GDF 15. Conclusion AH displays a specific fibrosis profile and protein signature. AH organoids and YAP-transduced Cirrh organoids induce myofibroblast activation. Hepatocyte YAP activation plays an important role in the fibrogenesis observed in AH. Impact and implications Aberrant activation of YAP in hepatocytes is involved in the impaired hepatocyte regeneration in AH by inducing their transdifferentiation toward a cholangiocyte-like phenotype. P reliminary data suggest that the composition of the ECM in AH is different from that of Cirrh with an increased laminin/fibronectin ratio. In a 3D coculture model of liver organoids and myofibroblasts, we showed that AH organoids (compared to Cirrh organoids) increased activation and proliferation of myofibroblasts. Aberrant YAP activation in altered hepatocytes is involved in the activation and proliferation of myofibroblasts in AH livers. Inhibiting YAP in hepatocytes could be an attractive approach in the development of treatments for AH to improve hepatic regeneration and decrease fibrogenesis.

Source: JHEP Reports

DOI: 10.1016/j.jhepr.2025.101580