PT  - JOURNAL ARTICLE
AU  - Kai You
AU  - Yan Wang
AU  - Xiaoxia Chen
AU  - Zhen Yang
AU  - Yan Chen
AU  - Shenglin Tan
AU  - Jiawang Tao
AU  - Anteneh Getachew
AU  - Tingcai Pan
AU  - Yingying Xu
AU  - Yuanqi Zhuang
AU  - Fan Yang
AU  - Xianhua Lin
AU  - Yinxiong Li
TI  - Serum Amyloid A promotes Acetaminophen-induced liver injury by damaging sinusoidal endothelial cell and exacerbating platelet aggregation in liver
AID  - 10.1101/2021.12.01.470869
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.12.01.470869
4099  - http://biorxiv.org/content/early/2021/12/03/2021.12.01.470869.short
4100  - http://biorxiv.org/content/early/2021/12/03/2021.12.01.470869.full
AB  - Background Acetaminophen (APAP) is the most commonly used non-prescription antipyretic and analgesic drugs. Overuse of APAP can cause hepatotoxicity. Liver sinusoidal endothelial cells (LSECs) damage is an important early event in APAP-induced liver injury. Serum amyloid A (SAA) is an acute phase protein that mainly produced by hepatocytes, and promotes endothelial dysfunction via a pro-inflammatory and pro-thrombotic effect in atherosclerosis and renal disease. However, the role of SAA in APAP-induced liver injury remains unclear.Methods In this study, we used neutralizing antibody (anti-SAA) or antagonistic small peptide derived from sequence of human SAA1/2 (SAA-pep) to block the functional activity of Saa1/2 in mouse serum. Immunohistochemistry staining, Evans blue and platelet adhesion assays were performed to examine the liver damage, the integrity of sinusoidal endothelium and platelets accumulation in APAP-induce liver injury.Results Our study showed that in the early stage of APAP-induced acute liver injury in mice, the intrahepatic and serum Saa1/2 levels were significantly increased within 24 hours, and then gradually reduced to normal level from 3 days. Neutralization of Saa1/2 by antibodies or peptides effectively prevented the destruction of hepatic sinusoids, reduced the intrahepatic hemorrhage and platelet accumulation in liver, as well as increased the survival rate of mice treated with lethal dose of APAP. In vitro experiments showed that Saa1/2 aggravated LSECs death induced by APAP. Moreover, Saa1/2 promoted platelets adhesion on LSECs via Tlr2/Vcam-1 axis.Conclusion Our findings suggest that Saa1/2 promotes APAP-induced liver injury by damaged LSECs and exacerbated platelets aggregation. This study provides a potential target for intervention of acute liver injury/failure caused by hepatotoxic drugs such as APAP.Competing Interest StatementThe authors have declared no competing interest.