Vitamin D receptor attenuates carbon tetrachloride-induced liver fibrosis via downregulation of YAP

作者：Ping Wang, Jie Li, Mintao Ji, Jinjing Pan, Yanmei Cao, Yulin Kong, Li Zhu, Jiafu Li, Bingyan Li, Lei Chang, Zengli Zhang · 发表于：Journal of Hazardous Materials · 年份：2024 · DOI：10.1016/j.jhazmat.2024.135480 · 被引用次数：29 · 研究领域：Liver physiology and pathology、Hippo pathway signaling and YAP/TAZ、Pancreatic function and diabetes

Liver fibrosis is characterized by the excessive accumulation of extracellular matrix proteins, which can lead to cirrhosis and liver cancer. Metabolic dysfunction-associated steatosis liver diseases are common causes of liver fibrosis, sharing a similar pathogenesis with carbon tetrachloride (CCl₄) exposure. This process involves the activation of hepatic stellate cells (HSCs) into myofibroblasts. However, the detailed mechanism and effective treatment strategies require further investigation. In this study, we uncovered a negative correlation between VDR expression and YAP within HSCs. Subsequently, we demonstrated that VDR exerted a downregulatory influence on YAP transcriptional activity in HSCs. Intriguingly, activation VDR effectively inhibited the culture induced activation of primary HSCs by suppressing the transcriptional activity of early YAP. Furthermore, in vivo results manifested that hepatic-specific deletion of YAP/TAZ ameliorates CCl4-induced liver fibrosis, and nullified the antifibrotic efficacy of VDR. Importantly, a YAP inhibitor rescued the exacerbation of liver fibrosis induced by hepatic-specific VDR knockout. Moreover, the combined pharmacological of VDR agonist and YAP inhibitor demonstrated a synergistic effect in diminishing CCl4-induced liver fibrosis, primary HSCs activation and hepatic injury in vivo. These effects were underpinned by their collective ability to inhibit HSC activation through AMPK activation, consequently curbing ATP synthesis an...