Plasma Fibulin-5 as a Novel Marker for Advanced Fibrosis in Chronic Hepatitis C.

Background and Aims: Despite remarkable advances in the treatment of viral hepatitis, liver fibrosis sometimes persists after viral eradication. The accumulation of elastic fiber is associated with unfavorable clinical outcomes. We aimed to clarify the utility of plasma fibulin-5 (FBLN5), a component of elastic fibers, in assessing liver fibrosis in patients with chronic hepatitis. Methods: We reviewed 90 patients with chronic hepatitis C who underwent liver biopsy. Using immunohistochemistry and in situ hybridization, we investigated the localization of FBLN5 and its correlation with α-smooth muscle actin (αSMA). We then analyzed mRNA and protein expression in human hepatic stellate cells (HHSteCs) and primary mouse stellate cells. Lastly, we evaluated the utility of plasma FBLN5 for predicting liver fibrosis in patients with hepatitis C. Results: Immunohistochemical analysis revealed a correlation between the quantity of FBLN5 and αSMA (r = 0.65) as well as FBLN5 and fibrosis stage (r = 0.30). FBLN5 was localized to areas enriched for αSMA-positive cells. In situ hybridization confirmed the colocalization of FBLN5 mRNA with αSMA and desmin-positive cells. Single nuclear RNA-sequencing analysis revealed that FBLN5 expression is predominantly expressed in the hepatic stellate cell/fibroblast cluster in other etiology, and the expression level was higher in cirrhotic livers. FBLN5 was overexpressed in cultured HHSteCs in response to 2.0 μg/mL transforming growth factor-β1 (P < .001), with increased FBLN5 concentration in the medium of transforming growth factor-β1-treated activated HHSteC. FBLN5 upregulation was also confirmed in primary-cultured mouse stellate cells. Finally, plasma FBLN5 levels increased with fibrosis progression in patients with chronic hepatitis C (P < .001). Conclusion: FBLN5 may represent the activation of hepatic stellate cells, and plasma FBLN5 levels have the potential to predict advanced fibrosis, especially in fibrosis related to elastic fibers.