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

• Published in: Experimental & molecular medicine 2022, 54(0), , pp.739-752
• Main Authors: Kim, Sun Myoung, Song, Ga Yeon, Shim, Aeri, Lee, Jee Hyung, Eom, Cheol Bin, Liu, Cheng, Yang, Yoon Mee, Seki, Ekihiro
• Format: Article
• Language: English
• Subjects: 13/109; 13/21; 13/51; 13/89; 3' Untranslated regions; 38/90; 64/60; 692/420/256/2515; 692/699/1503/1607/1605; Animal models; Animals; Bile ducts; Biomedical and Life Sciences; Biomedicine; Carbon tetrachloride; Carbon Tetrachloride - adverse effects; CCL3 protein; CCL4 protein; Cell activation; Chemokine CCL3 - metabolism; Chemokine CCL4 - metabolism; Enzymes; Extracellular matrix; Fibrosis; Hepatic Stellate Cells - metabolism; Hyaluronan synthase; Hyaluronan Synthases - genetics; Hyaluronan Synthases - metabolism; Hyaluronic acid; Hyaluronic Acid - adverse effects; Hyaluronic Acid - metabolism; Inflammation; Inflammation - metabolism; Liver; Liver Cirrhosis - chemically induced; Liver Cirrhosis - genetics; Liver Cirrhosis - metabolism; Macrophages; Medical Biochemistry; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Molecular Medicine; Polymers; Post-transcription; Stem Cells; Therapeutic targets; Wound healing; 생화학
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-022-00781-5

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: CCl 4 -induced acute liver injury, CCl 4 -induced chronic liver fibrosis, and bile duct ligation-induced liver fibrosis. Hepatic Has2 expression was induced by acute and chronic CCl 4 treatment. In contrast, miR-200c expression was decreased after CCl 4 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. Liver fibrosis: Targeting polymer-producing enzyme could alleviate liver scarring The molecular regulation of an enzyme involved in extracellular matrix production in liver tissues offers a promising therapeutic target for treating fibrosis. A team led by Ekihiro Seki from Cedars-Sinai Medical Center in Los Angeles, USA, and Yoon Mee Yang from Kangwon National University in Chuncheon, South Korea, found that a small regulatory RNA molecule called miR-200c represses the expression of hyaluronan synthase 2 (HAS2), an enzyme that stitches sugar molecules together to create a carbohydrate polymer found in the extracellular matrix th