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Volume 20
Issue 24
10.3390/ijms20246301
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Article

4-methylumbelliferone Prevents Liver Fibrosis by Affecting Hyaluronan Deposition, FSTL1 Expression and Cell Localization

by
Irina N. Andreichenko
1,†,
Alexandra A. Tsitrina
2,†,
Alexander V. Fokin
2,
Adelya I. Gabdulkhakova
1,
Dmitry I. Maltsev
2,
Grigorii S. Perelman
1,
Elena V. Bulgakova
2,
Alexey M. Kulikov
2,
Arsen S. Mikaelyan
2,* and
Yuri V. Kotelevtsev
1,*
1
Center for Neurobiology and Brain Restoration, Skolkovo Institute of Science and Technology, Skolkovo, 143025 Moscow, Russia
2
Koltzov Institute of Developmental Biology of Russian Academy of Sciences, 26 Vavilov Street, 119334 Moscow, Russia
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to the work.
Int. J. Mol. Sci. 2019, 20(24), 6301; https://doi.org/10.3390/ijms20246301
Received: 27 November 2019 / Accepted: 12 December 2019 / Published: 13 December 2019
(This article belongs to the Special Issue Role of Hyaluronan, Hyaluronan Receptors and Binding Partners in Health and Disease)
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Abstract

4-methylumbelliferone (4MU) is an inhibitor of hyaluronan deposition and an active substance of hymecromone, a choleretic and antispasmodic drug. 4MU reported to be anti-fibrotic in mouse models; however, precise mechanism of action still requires further investigation. Here we describe the cellular and molecular mechanisms of 4MU action on CCl4-induced liver fibrosis in mice using NGS transcriptome, Q-PCR and immunohistochemical analysis. Collagen and hyaluronan deposition were prevented by 4MU. The CCl4 stimulated expression of Col1a and αSMA were reduced, while the expression of the ECM catabolic gene Hyal1 was increased in the presence of 4MU. Bioinformatic analysis identified an activation of TGF-beta and Wnt/beta-catenin signaling pathways, and inhibition of the genes associated with lipid metabolism by CCL4 treatment, while 4MU restored key markers of these pathways to the control level. Immunohistochemical analysis reveals the suppression of hepatic stellate cells (HSCs) transdifferentiation to myofibroblasts by 4MU treatment. The drug affected the localization of HSCs and macrophages in the sites of fibrogenesis. CCl4 treatment induced the expression of FSTL1, which was downregulated by 4MU. Our results support the hypothesis that 4MU alleviates CCl4-induced liver fibrosis by reducing hyaluronan deposition and downregulating FSTL1 expression, accompanied by the suppression of HSC trans-differentiation and altered macrophage localization. View Full-Text
Keywords: liver fibrosis; 4-methylumbelliferone; hyaluronan; hyaluronan synthase; FSTL1 liver fibrosis; 4-methylumbelliferone; hyaluronan; hyaluronan synthase; FSTL1
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MDPI and ACS Style

Andreichenko, I.N.; Tsitrina, A.A.; Fokin, A.V.; Gabdulkhakova, A.I.; Maltsev, D.I.; Perelman, G.S.; Bulgakova, E.V.; Kulikov, A.M.; Mikaelyan, A.S.; Kotelevtsev, Y.V. 4-methylumbelliferone Prevents Liver Fibrosis by Affecting Hyaluronan Deposition, FSTL1 Expression and Cell Localization. Int. J. Mol. Sci. 2019, 20, 6301. https://doi.org/10.3390/ijms20246301

AMA Style

Andreichenko IN, Tsitrina AA, Fokin AV, Gabdulkhakova AI, Maltsev DI, Perelman GS, Bulgakova EV, Kulikov AM, Mikaelyan AS, Kotelevtsev YV. 4-methylumbelliferone Prevents Liver Fibrosis by Affecting Hyaluronan Deposition, FSTL1 Expression and Cell Localization. International Journal of Molecular Sciences. 2019; 20(24):6301. https://doi.org/10.3390/ijms20246301

Chicago/Turabian Style

Andreichenko, Irina N., Alexandra A. Tsitrina, Alexander V. Fokin, Adelya I. Gabdulkhakova, Dmitry I. Maltsev, Grigorii S. Perelman, Elena V. Bulgakova, Alexey M. Kulikov, Arsen S. Mikaelyan, and Yuri V. Kotelevtsev. 2019. "4-methylumbelliferone Prevents Liver Fibrosis by Affecting Hyaluronan Deposition, FSTL1 Expression and Cell Localization" International Journal of Molecular Sciences 20, no. 24: 6301. https://doi.org/10.3390/ijms20246301

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