The chemokine CCL20 promotes hepatocyte cholesterol deposition during metabolic dysfunction-associated steatohepatitis by regulating OLR1 expression.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is becoming a leading driver of liver failure and transplantation. The specific pathogenic mechanisms driving MASH remain incompletely understood. In this study, we aimed to investigate the role of CCL20 in MASH progression.

METHODS

Using RNA sequencing data and murine models of MASH, we analyzed the expression levels of CCL20 in liver tissues, as well as the correlation of CCL20 levels with liver function parameters. Hepatic CCL20-knockdown and hepatic progenitor cell (HPC)/cholangiocyte-specific CCL20-knockout mice were used to assess the role of CCL20 in hepatic steatosis and inflammation. The mechanisms by which CCL20 influences MASH were explored via in vitro and in vivo gain- and loss-of-function approaches.

RESULTS

We observed that CCL20 is significantly upregulated in MASH livers from mice and humans and that hepatic CCL20 expression is positively correlated with MASH severity. CCL20, which is mainly produced by HPCs/cholangiocytes, is transcriptionally activated by RELB and SOX9. In mice, CCL20 knockout in HPCs/cholangiocytes attenuated pathological changes in the liver. Mechanistically, by binding to CCR6, CCL20 activates the JNK signaling pathway, which increases OLR1 expression, thereby promoting oxLDL uptake and cholesterol deposition in hepatocytes.

CONCLUSION

These findings implicate the CCL20-CCR6-JNK-OLR1 axis as a crucial determinant of MASH progression and highlight CCL20 inhibition as an attractive therapeutic strategy for MASH.