Liquiritigenin suppresses the activation of hepatic stellate cells via targeting miR-181b/PTEN axis

Phytomedicine. 2020 Jan:66:153108. doi: 10.1016/j.phymed.2019.153108. Epub 2019 Oct 4.

Abstract

Background: Liquiritigenin (LQ), an aglycone of liquiritin in licorice, has demonstrated antioxidant, anti-inflammatory and anti-tumor activities. Previously, LQ was found to inhibit liver fibrosis progression.

Purpose: Phosphatase and tensin homolog (PTEN) has been reported to act as a negative regulator of hepatic stellate cell (HSC) activation. However, the roles of PTEN in the effects of LQ on liver fibrosis have not been identified to date.

Methods: The effects of LQ on liver fibrosis in carbon tetrachloride (CCl4) mice as well as primary HSCs were examined. Moreover, the roles of PTEN and microRNA-181b (miR-181b) in the effects of LQ on liver fibrosis were examined.

Results: LQ markedly ameliorated CCl4-induced liver fibrosis, with a reduction in collagen deposition as well as α-SMA level. Moreover, LQ induced an increase in PTEN and effectively inhibited HSC activation including cell proliferation, α-SMA and collagen expression, which was similar with curcumin (a positive control). Notably, loss of PTEN blocked down the effects of LQ on HSC activation. PTEN was confirmed as a target of miR-181b and miR-181b-mediated PTEN was involved in the effects of LQ on liver fibrosis. LQ led to a significant reduction in miR-181b expression. LQ-inhibited HSC activation could be restored by over-expression of miR-181b. Further studies demonstrated that LQ down-regulated miR-181b level via Sp1. Collectively, we demonstrate that LQ inhibits liver fibrosis, at least in part, via regulation of miR-181b and PTEN.

Conclusion: LQ down-regulates miR-181b level, leading to the restoration of PTEN expression, which contributes to the suppression of HSC activation. LQ may be a potential candidate drug against liver fibrosis.

Keywords: Hepatic stellate cell; Liquiritigenin; Liver fibrosis; PTEN; miR-181b.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Antioxidants / pharmacology*
  • Carbon Tetrachloride / adverse effects
  • Cell Proliferation / drug effects
  • Down-Regulation
  • Flavanones / pharmacology*
  • Glycyrrhiza / chemistry*
  • Hepatic Stellate Cells / drug effects
  • Humans
  • Hydroxyproline / analysis
  • Immunohistochemistry
  • Liver / drug effects
  • Liver / metabolism
  • Liver Cirrhosis / drug therapy*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*

Substances

  • Anti-Inflammatory Agents
  • Antioxidants
  • Flavanones
  • MicroRNAs
  • mirn181 microRNA, mouse
  • Carbon Tetrachloride
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • Hydroxyproline
  • liquiritigenin