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Skolkovo Institute for Science and Technology, Russia
Title: 4-Methylumbelliferone reduces liver fibrosis in CCl4-treated mice and prevents hepatocyte necrosis caused by paracetamol.

Adelya Gabdulkhakova has graduated from Sechenov Medical University in 2016 and studies Translational Biomedicine at Skolkovo Institute of Science and Technology, Moscow. The focus of her research is on the pathophysiology of hepatocytes damage.


Background and aims: Liver fibrosis is a potentially morbid condition with the unmet therapeutic needs. Previously, in vivo siRNA silencing of hyaluronan synthase 2 (HAS2) in CCL4-treated mice reduced liver fibrosis but augmented myofibroblast density. This prompted us to investigate the therapeutic potential of 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan production, on liver fibrosis, hyaluronan deposition and expression of profibrotic genes in a chemically induced liver injury.
Methods: 8-week old female BALB/c mice (n=8 per group) were subjected to liver injury by CCl4 inhalation twice a week for 15 mins, for 2 or 4 weeks. 4-MU (800 mg/kg) was given daily by gavage starting i) two weeks before CCL4 inhalation; ii) simultaneously with CCl4; iii) 2 weeks after the start of CCL4 treatment; iv) for 2 weeks after the discontinuation of CCL4 treatment. In all groups, 4-MU treatment continued until sample collection.
Paracetamol (450 mg/kg, by gavage) was given daily for 1 month to a separate set of mice, with or without 4-MU (800 mg/kg). The liver lobes were collected at different time points to assess mRNA levels of myofibroblast-specific genes expression by qPCR and for histological analysis. The extent of fibrosis was evaluated using Mallory staining. Hyaluronan, collagen and alpha smooth muscle actin (?SMA) were revealed immunohistochemically. The images were taken with a Keyence BZ9000 microscope and processed with ImageJ software.
Results: The area of fibrosis in the CCl4 experimental group pretreated with 4-MU was reduced by 55%, as assessed by Mallory staining. Smaller but still significant effects of 4-MU were registered when applied after the liver injury was established. The expression levels of myofibroblast-specific genes Fstl1, ?SMA and Col1 were maximally upregulated (up to 3 fold) after 2 weeks of CCL4 inhalation and reduced in all experimental groups administered with 4-MU. Discontinuation of CCl4 inhalation also demonstrated decreased levels of gene expression, but the effect was enhanced in the group treated with 4-MU. Immunofluorescent staining revealed reduced ?SMA expression, and colocalized collagen and hyaluronan deposition in 4-MU-treated mice. Paracetamol caused extensive necrosis but did not induce significant fibrosis, and necrosis was dramatically reduced in mice treated with 4-MU. Adding 4-MU to TGFb2-stimulated 3T3 fibroblasts in vitro reduced both HAS2 and hyaluronidase 2, and increased hyaluronidase 1 expression.
Conclusion: 4-MU protects hepatocytes from CCL4- and paracetamol–induced injury. 4-MU treatment reverses the established fibrosis and accelerates the liver regeneration via a reduced activity of myofibroblast-specific genes. These results suggest 4-MU to be a promising candidate for both preventing and treating liver fibrosis and to be further tested in clinical trials.

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