| Invited Lecture(JSGE) |
| Sat. November 23rd 14:00 - 14:30 Room 2: Kobe International Exhibition Hall No.2 Building Hall (South) |
| Inflammation and extracellular matrix regulation of liver fibrosis | |||
| Ekihiro Seki | |||
| Cedars-Sinai Medical Center | |||
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| Backgrounds: Hyaluronan (HA), a major extracellular matrix glycosaminoglycan, have been used as a biomarker for cirrhosis. Although dysfunction of HA clearance in cirrhosis has been documented, the regulatory mechanism of HA synthesis and the effect of overproduction of HA in liver fibrosis are poorly understood. This study provides evidence that HA is actively synthesized by HA synthase 2 (HAS2) in hepatic stellate cells (HSCs) and promotes HSC activation and liver fibrosis. Methods: HA and HAS2 expression was examined in blood and fibrotic liver specimens from patients with hepatitis B (n=65), hepatitis C (n=55), and non-alcoholic steatohepatitis (NASH; n=24). HSC-specific Has2 knockout mice (Has2ΔHSC) were generated by crossing Has2 flox mice with Lrat-Cre mice. Acta2 promoter-driven HAS2Tg mice were also used. Liver fibrosis was induced by bile duct ligation (BDL), chronic carbon tetrachloride (CCl4) treatment, and choline-deficient high-fat diet (CDHFD) feeding. RNA-sequencing analysis, proliferation and invasion assays were performed using Has2-/- and HAS2Tg HSCs. Results: Hepatic HAS2 expression and blood HA levels were elevated in liver fibrosis of hepatitis B, hepatitis C, and NASH in humans, and in liver fibrosis induced by BDL, CCl4 treatment, and CDHFD feeding in mice. HAS2Tg mice had augmented HA production and liver fibrosis while Has2ΔHSC mice showed reduced HA production and liver fibrosis. HAS2-mediated fibrogenic (Col1A1 and Acta2 expression), proliferative, and invasive phenotypic changes in HSCs were mediated through the HA receptors CD44 and TLR4. The biological actions of HA depend on its molecular size. Our data showed that low-molecular weight (LMW)-HA is the dominant form of HA in mouse fibrotic livers and in the blood from patients with liver fibrosis. In fact, LMW-HA promoted fibrotic and inflammatory response in HSCs. The RNA-sequencing analysis revealed that HAS2, CD44, and TLR4 are associated with induction of Notch-associated gene expression. Indeed, Notch1 mediates HSC activation and mice lacking Notch1 in HSCs had reduced liver fibrosis. In HSCs, increased HAS2 expression was mediated via transcriptional upregulation of transforming growth factor-β through Wilms tumor 1. Treatment of 4-methylumbelliferone, an inhibitor of HA synthesis, mitigated BDL- and NASH-induced liver fibrosis. Conclusion: Our study demonstrated that overexpressed HAS2 and HA promote HSC activation and liver fibrosis through Notch1 and that inhibiting HA synthesis has potential to be an effective therapy for liver fibrosis. |
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