Affiliation:
1. Anhui Medical University First Affiliated Hospital Department of Medical Oncology
2. Anhui Medical University
3. Anhui Provincial Hospital
Abstract
Abstract
Background
Previous studies have shown that bone morphogenetic protein 9 (BMP9) is almost exclusively produced in the liver and reaches tissues throughout the body as a secreted protein. However, the role and mechanism of BMP9 in aging-associated liver injury and inflammation are still unclear.
Results
Aging significantly aggravates acetaminophen (APAP)-induced acute liver injury (ALI). Increased expression of CCAAT/enhancer binding proteins α (C/EBPα) and BMP9 was detected in the aged livers, as well as in hepatocytes and macrophages (MФs) isolated from the aged mice. The current results showed that excess BMP9 is directly related to APAP-induced hepatocyte injury and death, evidenced by activated drosophila mothers against decapentaplegic protein 1/5/9 (SMAD1/5/9) signal, higher cell death ratio, inhibited ATG3 and ATG7, blocked autophagy, increased activity of senescence-associated beta‐galactosidase (SA‐β‐Gal), and increased senescence‐associated secretory phenotype (SASP). Conversely, Bmp9 knockout (Bmp9−/−) could partly alleviate the above signs. Moreover, the expression of BMP9 was found to be regulated by C/EBPα in vitro and in vivo. Notably, BMP9 can also downregulated autophagy through autophagy-related genes (ATG3 and ATG7) in MΦs, which is associated with the aggravation of liver injury and the production of SASP.
Conclusions
In summary, the present study highlights the crucial roles for the C/EBPα-BMP9 crosstalk and provides insights into the interrelationship between hepatocytes and MΦs during acute liver injury.
Publisher
Research Square Platform LLC
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