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The anti‐apoptotic activity of protein S worsens liver fibrosis by activating the Akt pathway
Author(s) -
Totoki Toshiaki,
D'AlessandroGabazza Cori.,
Toda Masaaki,
Takeshita Atsuro,
Yasuma Taro,
Nishihama Kota,
Horiki Noriyuki,
Takei Yoshiyuki,
Gabazza Esteban C
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.lb555
Subject(s) - hepatic stellate cell , liver injury , apoptosis , fibrosis , protein kinase b , carbon tetrachloride , chemokine , medicine , endocrinology , cancer research , chemistry , inflammation , biochemistry , organic chemistry
Protein S is a vitamin K‐dependent glycoprotein produced mainly in the liver with anticoagulant, anti‐inflammatory, immune‐modulatory and anti‐apoptotic properties. The anti‐apoptotic activity of protein S can ameliorate or worsen a disease state depending on the organ involved. For example, protein S attenuates pulmonary fibrosis by inhibiting apoptosis of lung alveolar epithelial cells or improve diabetes mellitus by inhibiting apoptosis of pancreatic islet b‐cells. On the contrary, exogenous protein S exerts detrimental effects during acute alcoholic hepatitis by its ability to activate and prolong the survival of liver natural killer T cells. In the present study, 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 and the degree of liver injury and fibrotic changes were evaluated. Human protein S transgenic mice receiving carbon tetrachloride showed significantly higher circulating levels of liver transaminases, increased liver expression of inflammatory cytokines and chemokines, significantly much extended liver fatty degeneration and fibrosis and increased areas with DNA breakage after chronic injury compared to wild‐type mice. Liver injury was also exacerbated in mice after one bolus injection of carbon tetrachloride. Wild‐type mice infused with exogenous human protein S exhibited exacerbated liver injury, had significantly less apoptosis associated with increased number of hepatic stellate cells compared to untreated mice. An in vitro study using primary human hepatic stellate cells demonstrated that protein S inhibits apoptosis and increases the degree of Akt pathway phosphorylation in these liver cells. Western analysis showed significantly less cleavage of caspase‐3 in liver tissue from protein S transgenic mice compared to wild type mice. In conclusion, the results of this investigation showed that the anti‐apoptotic activity of protein S may play a role in chronic liver injury and subsequent liver fibrosis. Support or Funding Information I have no financial relationships to disclose. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .