Liver fibrosis is the result of chronic liver injury and the first step toward the development of liver cirrhosis and hepatic carcinoma. Under the stress of damage factors, quiescent hepatic stellate cells (qHSCs) trans-differentiate into myofibroblast-like cells, and take the main role of extracellular matrix secretion contributing to the development of liver fibrosis. In recent clinical study, circulating level of A-FABP, was found to positively correlate with the stages of liver fibrosis and liver cirrhosis. Here, we investigate the role of A-FABP in the development of liver fibrosis. A-FABP knockout (A-FABP KO) mice and their wild type (WT) littermates were subjected to bile duct ligation (BDL) for two weeks to induce liver fibrosis. Plasma and hepatic A-FABP were significantly elevated in BDL treated WT mice. Liver sinusoidal endothelial cell (LSEC) was identified as the major cellular source of hepatic A-FABP in response to BDL. In the BDL treated groups, comparing to the WT mice, A-FABP KO mice showed significantly reduced collagen formation and HSC activation which were accompanied by an attenuated induction of hepatic expression of transforming growth factor beta 1 (TGFβ1), a central regulator in hepatic fibrogenesis. As the LSECs and HSCs are closely attached to each other, we hypothesize that LSECs-derived A-FABP may act in a paracrine manner to stimulate the expression of TGFβ1 in HSCs. Our in vitro study demonstrated that treatment of recombinant A-FABP protein (rA-FABP) significantly induced the expression of TGFβ1 in primary HSCs. Mechanistically, BDL induces the release of A-FABP from LSECs which stimulates the TGFβ1 gene transcription through enhancing the activator protein-1 (AP-1) activity on its promoter via upregulating the phosphorylation of c-Jun, a component of AP-1.
In conclusion, A-FABP contributes to the development of liver fibrosis via enhancing the expression of TGFβ1 in HSCs.
X. Wu: None. L. Shu: None. K.S. Lam: None. A. Xu: None. R. Hoo: None.