Fibrinogen-like protein 1 is a hepatoprotectant
Chinweike Ukomadu1, Anal Desai1, Valeriy Demchev1, Hamed Nayeb-Hashemi1, Agoston Agoston1, Xintong Chen2, Joana F. Neves1, Richard S. Blumberg1, Yujin Hoshida2
1Brigham and Women's Hospital, Boston, MA; 2Medicine, Icahn School of Medicine at MT. Sinai, New York, NY
Background: Fibrinogen like protein 1(Fgl1) is a hepatocyte secreted protein whose expression increases following acute liver injury. Fgl1 stimulates uptake of tritiated thymidine into hepatocytes and activates pathways involved in hepatocyte proliferation. As such, it is believed that Fgl1 functions as a hepatocyte mitogen. We previously showed that Fgl1 is an acute phase protein and have recently generated mice with targeted loss of Fgl1.Aim: To determine the role of Fgl1 during liver injury. Methods: We used two acute injury models. 1)We evaluated mice wild type (Fgl1+/+) or null (Fgl1-/-) for Fgl1 at 24 hour intervals (0 h-120 h) following a one-time administration of CCL4 (0.4 mg/kg). 2) We administered alpha-galactosylceramide (α-GalCer) (2μg/mouse), an inducer of natural killer T cell mediated liver injury to Fgl1 +/+ and Fgl1-/- mice. We determined ALT levels and collected liver tissue at 24 h post injection. For chronic liver injury, we injected mice twice weekly with CCL4 (0.2 mg/kg) for four weeks and then performed gene-expression microarray analyses on liver tissues. We used gene set enrichment analysis to identify biologic pathways affected by Fgl1.Results: Following acute CCL4 administration we found a lag in the time to repair of liver injury in the Fgl 1-/mice, with injury in Fgl 1 +/+ largely resolved by 72 h post injection while it persisted until 120 h in the Fgl1-/- mice. We found no difference in hepatocyte proliferation by PCNA staining, suggesting that this effect is not due to loss of Fgl1 mitogenic activity. We found no differences in the number, morphology and distribution of bile ducts, stellate cells and endothelial cells by immunohistochemistry. Mice treated with αGalCer also showed a 4 fold increase in ALT and marked hepatocellular necrosis in Fgl1-/- when compared to the Fgl1+/+ mice. Consistent with a role in protection from inflammatory liver injury, chronic administration of CCL4 results in a more sustained inflammatory injury. Gene-expression microarray data implicate pathways involved in inflammation and hepatocyte injury (for example Toll, NFKB, IL22 soluble receptor and IL1 receptor pathways) as upregulated in the Fgl1 null mice. Conclusions: Mice with targeted deletion of Fgl1 have more pronounced acute and chronic liver injury when compared to wild type mice. Gene expression data suggest that pathways that protect hepatocytes from injury are perturbed in the Fgl1 null mice. Given its role as an acute phase reactant, we speculate that Fgl1 is enhanced following injury to protect hepatocytes from damage. Future studies will delineate specific immunologic targets of Fgl1.
Chinweike Ukomadu - Consulting: Gilead Sciences
The following people have nothing to disclose: Anal Desai, Valeriy Demchev, Hamed Nayeb-Hashemi, Agoston Agoston, Xintong Chen, Joana F. Neves, Richard S. Blumberg, Yujin Hoshida