Abstract
The liver-enriched transcription factor Forkhead Box A2 (FOXA2) has been reported to be involved in bile acid homeostasis and bile duct development. However, the role of FOXA2 in liver fibrogenesis remains undefined. In this study, we found that the abundance of FOXA2 was significantly lower in fibrotic livers of patients and mice treated with CCl4 than in controls. Interestingly, the expression level of FOXA2 decreased in hepatocytes, whereas FOXA2 was elevated in hepatic stellate cells (HSCs) of mouse fibrotic livers. Hepatocyte-specific ablation of FOXA2 in adult mice exacerbated liver fibrosis induced by CCl4. Either lentivirus LV-CMV-FOXA2 mediated FOXA2 overexpression in the liver or adeno-associated virus AAV8-TBG-FOXA2-mediated hepatocyte-specific upregulation of FOXA2 alleviated hepatic fibrosis. Overexpression of FOXA2 in HSCs did not obviously affect hepatic fibrogenesis. Additionally, FOXA2 knockout in hepatocytes resulted in aberrant transcription of metabolic genes. Furthermore, hepatocyte-specific knockout of FOXA2 enhanced endoplasmic reticulum stress (ER stress) and the apoptosis of hepatocytes, whereas FOXA2 overexpression in hepatocytes suppressed ER stress and hepatocyte apoptosis in mouse fibrotic livers. In conclusion, our findings suggested that FOXA2-mediated hepatocyte protection has a therapeutic role in hepatic fibrosis, and thus may be a new, promising anti-fibrotic option for treating chronic liver diseases.
Highlights
Various chronic liver injuries induced by persistent infections, alcohol abuse, chemical insults, and metabolic or autoimmune reactions can give rise to fibrosis, cirrhosis, liver failure and even tumour formation[1,2,3]
By using three distinct viruses to deliver the expression of Forkhead box A2 (FOXA2) into the liver, we found that FOXA2 attenuated liver fibrosis by protecting hepatocytes from endoplasmic reticulum stress (ER stress) and apoptosis
These findings indicated that progressive liver fibrosis is associated with decreased FOXA2 expression
Summary
Various chronic liver injuries induced by persistent infections, alcohol abuse, chemical insults, and metabolic or autoimmune reactions can give rise to fibrosis, cirrhosis, liver failure and even tumour formation[1,2,3]. Recent studies have indicated that HSCs play a critical role in the process of liver development and regeneration[5]. Transcription factor network in hepatocytes by HNF4α reverses dysfunctional hepatocytes and hepatic failure[12] Together, these data suggest that HNFs may be potential therapeutic targets for treating liver fibrosis. FOXA2 cooperates with FOXA1 ( known as HNF3α) to establish competence in the foregut endoderm and is required for the initiation of liver development[14]. One recent study has demonstrated that FOXA2 mediates the therapeutic effects of biliary-committed progenitor cells during cholestatic liver injury[20]. We generated mutant mice in which FOXA2 was deleted in hepatocytes and demonstrated that FOXA2 knockout in hepatocytes exacerbated liver fibrosis induced by CCl4. By using three distinct viruses to deliver the expression of FOXA2 into the liver, we found that FOXA2 attenuated liver fibrosis by protecting hepatocytes from endoplasmic reticulum stress (ER stress) and apoptosis
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