Abstract
Liver fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM), primarily produced by activated hepatic stellate cells (HSCs). The activation of HSCs is influenced by paracrine signaling interactions among various liver cell types, but molecular mechanisms remain to be elucidated. Secretory Meteorin-like (Metrnl) can effectively ameliorate fulminant hepatitis. However, little is known about its role in liver fibrosis. In our study, we found that hepatic Metrnl mRNA transcripts and protein expression were significantly downregulated in patients and mouse models of hepatic fibrosis. Hepatocyte-specific and global knockout of Metrnl exacerbated CCl4-induced liver fibrosis. In contrast, the administration recombinant Metrnl or AAV-Metrnl overexpression markedly ameliorated CCl4-induced liver fibrosis in mice, suggesting a protective role for Metrnl. Mechanistically, hepatocyte-derived Metrnl not only influences the activation of HSCs through paracrine signaling but also modulates the release of the fibrogenic cytokine PDGFB via the transcription factor EGR1, thereby regulating PDGFB/PDGFRβ signaling to affect HSC activation. Furthermore, Metrnl absence in hepatocytes and HSCs leads to the downregulation of the E3 ubiquitin ligase HECW2, inhibiting K48-linked ubiquitination of FN and preventing its proteasomal degradation, thus promoting FN secretion from HSCs. These effects contribute to ECM deposition and the activation of HSCs, ultimately exacerbating liver fibrosis. Collectively, our study reveals Metrnl as a novel regulator of liver fibrosis that mediates communication between hepatocytes and HSCs, indicating its potential as a therapeutic target for liver fibrosis. The identification of Metrnl as a critical player in the pathogenesis of hepatic fibrosis underscores the importance of understanding cellular crosstalk in the progression of liver disease.