Hyaluronan synthase 2, a target of miR-200c, promotes carbon tetrachloride-induced acute and chronic liver inflammation via regulation of CCL3 and CCL4

Abstract

Liver fibrosis occurs during wound healing after repeated liver injury and is characterized by extensive extracellular matrix deposition. We previously identified hyaluronan synthase 2 (HAS2) as a driver of liver fibrosis and hepatic stellate cell (HSC) activation. Developing strategies to suppress HSC activation is key to alleviating liver fibrosis, and HAS2 is an attractive candidate for intervention. To gain insight into the molecular function of HAS2, we investigated its posttranscriptional regulation. We found that miR-200c directly targets the 3’ untranslated regions of HAS2. Moreover, miR-200c and HAS2 were inversely expressed in fibrotic human and mouse livers. After establishing the direct interaction between miR-200c and HAS2, we investigated the functional outcome of regulating HAS2 expression in three murine models: CCl4-induced acute liver injury, CCl4-induced chronic liver fibrosis, and bile duct ligation-induced liver fibrosis. Hepatic Has2 expression was induced by acute and chronic CCl4 treatment. In contrast, miR-200c expression was decreased after CCl4 treatment. HSC-specific Has2 deletion reduced the expression of inflammatory markers and infiltration of macrophages in the models. Importantly, hyaluronidase-2 (HYAL2) but not HYAL1 was overexpressed in fibrotic human and murine livers. HYAL2 is an enzyme that can cleave the extracellular matrix component hyaluronan. We found that low-molecular-weight hyaluronan stimulated the expression of inflammatory genes. Treatment with the HA synthesis inhibitor 4-methylumbelliferone alleviated bile duct ligation-induced expression of these inflammatory markers. Collectively, our results suggest that HAS2 is negatively regulated by miR-200c and contributes to the development of acute liver injury and chronic liver inflammation via hyaluronan-mediated immune signaling.

A thioacetamide-induced liver fibrosis model for pre-clinical studies in microminipig

“…Activated hepatic stellate cells (HSC) express hyaluronan synthase (HAS2) 38 , which is involved in the accumulation of HA in the liver. HAS2 and HA further promote HSC activation and fibrosis 38 , 39 and are detected in the blood of animals with advanced liver fibrosis 38 . In this study, HA levels were elevated in some individuals in the TAA group.…”

Analysis of potential immune-related genes involved in the pathogenesis of ischemia-reperfusion injury following liver transplantation

“…CCL4 belongs to the macrophage inflammatory protein-1 (MIP-1) family, which recruits immune cells and is produced by hepatic stellate cells, macrophages and monocytes, in the liver ( 35 ). Krohn et al.…”

“…CCL4 belongs to the macrophage inflammatory protein-1 (MIP-1) family, which recruits immune cells and is produced by hepatic stellate cells, macrophages and monocytes, in the liver (35). Krohn et al found that CCL4 plays an important role in the early induction of immune cell infiltration after hepatocyte transplantation (36).…”

Hyaluronan in liver fibrosis: basic mechanisms, clinical implications, and therapeutic targets

“…miR-200c is downregulated by liver fibrosis, binds to the 3’-UTR of HAS2, and post-transcriptionally regulates HAS2 expression in HSCs (Figure 5 ). 67 Hedgehog (Hh) signaling is another important pathway in HSC activation and liver fibrosis. In Hh signaling, the interaction of sonic Hedgehog ligand and the cell surface receptor Patched releases and activates Smoothened, leading to nuclear localization of glioblastoma family transcription factors (Glis) that regulate the expression of cell-specific target genes.…”