Abstract
BackgroundNon-canonical Wnt pathways play important roles in liver fibrosis. Notum is a newly discovered inhibitor to Wnt proteins. This study was to investigate anti-fibrotic effects of Notum.Methods53 patients with hepatitis B virus (HBV) infection as well as a cell co-culture system of LX-2 and Hep AD38 cells were engaged in this study. Clinical, biological and virological data of each patient were analyzed. Cell viability was detected at different time points. mRNA and protein levels of NFATc1 (Nuclear factor of activated T-cells), Jnk, α-SMA, Col1A1 and TIMP-1 were detected both in LX-2 and liver tissue. Protein levels of NFATc1 and Jnk in liver tissue and their correlations with fibrosis score were analyzed.ResultsHepatitis B virus replication up-regulated Wnt5a induced NFATc1 and Jnk activity in Hep AD38. Notum suppressed NFATc1, Jnk and fibrosis genes expression, reduced cell viability in co-cultured LX-2 cells induced by HBV. Interestingly, Patients with HBV DNA > 5log copies/ml had higher mRNA levels of NFATc1 and fibrosis genes than patients with HBV DNA < 5log copies/ml. Most importantly, protein expressions of NFATc1 and pJnk have positive correlations with liver fibrosis scores in HBV-infected patients.ConclusionsOur data showed that Notum inhibited HBV-induced liver fibrosis through down-regulating Wnt 5a mediated non-canonical pathways. This study shed light on anti-fibrotic treatment.
Highlights
Non-canonical Wnt pathways play important roles in liver fibrosis
Serum levels of alanine transaminase (ALT), aspartate transaminase (AST), lactic dehydrogenase (LDH) in patients were determined by routine laboratory tests in Anhui Provincial Hospital (Hefei, China)
We first determined whether Wnt 5a protein could induce LX-2 cell activation
Summary
Non-canonical Wnt pathways play important roles in liver fibrosis. Liver fibrosis was considered to be a wound-healing response of liver to chronic liver injuries including alcohol, hepatitis and immune compound. It was characterized by an excessive deposition of extracellular matrix (ECM) components in liver [1]. Activated hepatic stellate cell (HSCs), the main source of accumulated ECM, has been evidenced to be the predominant cell type responsible for liver fibrosis development. Repressing HSC activation may prevent and reverse liver fibrosis [2]. If treated properly at an early stage, HBV-induced liver fibrosis can be reversed [4, 5]. The mechanism of HBV-related liver fibrosis remains poorly understood
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