Knockdown of Yap attenuates TAA-induced hepatic fibrosis by interaction with hedgehog signals

Abstract

Liver fibrosis is an aberrant wound healing response to tissue injury characterized by excessive extracellular matrix deposition and loss of normal liver architecture. Hepatic stellate cells (HSCs) activation is regards to be the major process in liver fibrogenesis which is dynamic and reversible. Both Hippo signaling core factor Yap and Hedgehog (Hh) signaling promote HSCs transdifferentiation thereby regulating the repair process of liver injury. However, the molecular function of YAP and the regulation between Yap and Hh during fibrogenesis remain uncertain. In this study, the essential roles of Yap in liver fibrosis were investigated. Yap was detected to be increased in liver fibrotic tissue by the thioacetamide (TAA)-induced zebrafish embryonic and adult models. Inhibition of Yap by both embryonic morpholino interference and adult's inhibitor treatment was proved to alleviate TAA-induced liver lesions by and histology and gene expression examination. Transcriptomic analysis and gene expression detection showed that Yap and Hh signaling pathway have a cross talking upon TAA-induced liver fibrosis. In addition, TAA induction promoted the nuclear colocalization of YAP and Hh signaling factor GLI2α. This study demonstrates that Yap and Hh play synergistic protective roles in liver fibrotic response and provides new theoretical insight concerning the mechanisms of fibrosis progression.Ye Zhao and Huiling Wang have contributed equally to this work.

The Coming Age of Antisense Oligos for the Treatment of Hepatic Ischemia/Reperfusion (IRI) and Other Liver Disorders: Role of Oxidative Stress and Potential Antioxidant Effect

“…Studies have focused on the role of ASOs in parenchymal cells, primarily hepatocytes, that constitute the bulk of the liver tissue and resident hepatic KC macrophages. However, other liver cell types (e.g., hepatic stellate cells (HSCs), LSECs, and bile duct epithelial cells (cholangiocytes)) have been investigated recently [ 71 , 72 , 73 ].…”

Interplay between YAP/TAZ and metabolic dysfunction-associated steatotic liver disease progression

“…Cirrhosis is an end-stage liver fibrosis characterized by severe architectural distortion and impaired liver function. Accumulating evidence strongly links YAP/TAZ upregulation to the progression of fibrosis and the development of cirrhosis (Machado et al 2015 ; Chen et al 2018 ; Wang et al 2020 ; Zhao et al 2023 ). Analysis of liver tissues from patients with fibrosis and cirrhosis repetitively confirmed an increased YAP/TAZ activity compared to healthy livers throughout multiple cohorts.…”