Hepatocyte iron suppresses liver fibrosis via fibrolytic neutrophil recruitment in cholestasis.

BACKGROUND & AIMS: Although it is well documented that iron promotes hepatocyte death in chronic liver disease, recent studies have suggested that iron in hepatocytes also has a protective role against such disease. However, the mechanisms underlying this beneficial role of iron remain poorly understood.

METHODS

F-box and leucine-rich repeat protein 5 (FBXL5) is a substrate recognition component of the SCF E3 ligase complex that restricts intracellular iron levels. To investigate the role of hepatic iron in the pathogenesis of cholestatic liver disease, liver-specific FBXL5-deficient or control mice were fed a diet supplemented with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (n = 3-12). Moreover, matrix metalloproteinase (MMP)-9 expression and liver fibrosis were analyzed in liver specimens obtained from 37 patients with primary biliary cholangitis (PBC).

RESULTS

Liver-specific FBXL5-deficient mice, which exhibit hepatic iron overload, were protected against liver fibrosis in cholestatic liver disease (Sirius red+ area, 3.1% vs. 5.3%, p = 0.005) without a reduction in fibrogenesis. The upregulation of MMP9-mediated fibrolysis accounted for resistance against liver fibrosis in these mice. Iron promoted CXC-motif ligand 5 (CXCL5) mRNA expression in hepatocytes by 2.6-fold (p = 0.001), accelerating MMP9+ neutrophil recruitment. Mechanistically, iron decreased H3K27 methylation by 14% (p <0.05) and increased chromatin accessibility in the Cxcl5 promoter. Furthermore, there was an inverse association between MMP9 expression and liver fibrosis in patients with PBC (Sirius red+ area, 7.3% in the MMP9high group vs. 9.7% in the MMP9low group; p = 0.04).

CONCLUSIONS

Our data link hepatocyte iron with fibrolysis pathways in the setting of chronic liver disease. Thus, the present study provides insights into the pro-resolving roles of neutrophils in cholestatic liver disease.

IMPACT AND IMPLICATIONS: In this study, we show that hepatocyte iron suppresses liver fibrosis in cholestatic liver disease. Mechanistically, hepatocyte iron epigenetically upregulates CXCL5 expression, thereby promoting hepatic recruitment of MMP9+ fibrolytic neutrophils. In addition, hepatic MMP9 expression is inversely associated with liver fibrosis in patients with PBC. These findings reveal a protective role for hepatocyte iron and offer new therapeutic insights for chronic liver disease.