Protein S Exacerbates Chronic Liver Injury and Fibrosis.

Abstract

Protein S is a vitamin K-dependent glycoprotein produced mainly in the liver with anticoagulant, anti-inflammatory, immune-modulatory, and antiapoptotic properties. Protein S exacerbates acute liver injury by prolonging the survival of liver immune cells. However, the effect of protein S on chronic liver injury and fibrosis is unknown. Here, we investigated whether human protein S can affect chronic liver injury and fibrosis. Liver injury/fibrosis was induced by carbon tetrachloride injection in mice overexpressing human protein S and in wild-type mice. Human protein S transgenic mice receiving carbon tetrachloride showed significantly higher circulating levels of liver transaminases, increased liver expression of inflammatory cytokines, significantly more extended liver fibrosis, and areas with DNA breakage after chronic injury compared with wild-type mice. Wild-type mice infused with exogenous human protein S exhibited exacerbated liver injury and increased number of hepatic stellate cells compared with untreated mice. Human protein S inhibited apoptosis and increased Akt pathway activation in hepatic stellate cells. The antiapoptotic activity of protein S may play a role in chronic liver injury and subsequent liver fibrosis.

• Authors: Toshiaki Totoki, Corina N D' Alessandro-Gabazza, Masaaki Toda, Prince Baffour Tonto, Atsuro Takeshita, Taro Yasuma, Kota Nishihama, Motoh Iwasa, Noriyuki Horiki, Yoshiyuki Takei, Esteban C Gabazza
• Journal: The American journal of pathology (Am J Pathol) Vol. 188 Issue 5 Pg. 1195-1203 (05 2018) ISSN: 1525-2191 [Electronic] United States
• PMID: 29454753 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Protein S
• Carbon Tetrachloride

Topics

• Animals
• Apoptosis (physiology)
• Carbon Tetrachloride
• End Stage Liver Disease (chemically induced, metabolism, pathology)
• Fibrosis (metabolism, pathology)
• Hepatic Stellate Cells (metabolism, pathology)
• Liver (metabolism, pathology)
• Mice
• Mice, Transgenic
• Protein S (genetics, metabolism)
• Signal Transduction (physiology)