New Compound Helps Prevent Liver Cell Activation and Fibrosis

Jenn Hoskins
6th August, 2024

New Compound Helps Prevent Liver Cell Activation and Fibrosis

Image Source: Natural Science News, 2024

Key Findings

  • Researchers at Fudan University found that Luteolin-7-diglucuronide (L7DG) significantly reduces liver fibrosis in both cell and animal models
  • L7DG treatment decreased fibrotic markers like collagen 1, α-SMA, and fibronectin in liver cells
  • The study identified L7DG as a potent inhibitor of protein tyrosine phosphatase 1B (PTP1B), which helps reduce liver fibrosis by inhibiting hepatic stellate cell activation
Liver fibrosis is a major global health issue, contributing to significant morbidity and mortality. The condition is characterized by the excessive accumulation of extracellular matrix proteins, primarily driven by the activation of hepatic stellate cells (HSCs). Despite its prevalence, effective therapies to treat liver fibrosis are currently lacking. Recent research conducted by Fudan University has investigated the potential of Luteolin-7-diglucuronide (L7DG), a flavonoid derived from Perilla frutescens and Verbena officinalis, in mitigating liver fibrosis[1]. The study focused on the anti-fibrotic properties of L7DG and its underlying mechanisms. Researchers used both mouse primary hepatic stellate cells (pHSCs) and the human HSC line LX-2, activated by TGF-β1, as in vitro models of liver fibrosis. They found that co-treatment with L7DG at varying concentrations (5, 20, 50 μM) significantly reduced the expression of fibrotic markers such as collagen 1, α-SMA, and fibronectin, which are indicative of fibrosis. In addition to in vitro experiments, the study included in vivo liver fibrosis models induced by carbon tetrachloride (CCl4) challenge alone or in combination with a high-fat, high-cholesterol (HFHC) diet. Administration of L7DG (40, 150 mg·kg-1·d-1) over 4 or 8 weeks dose-dependently alleviated histopathological liver injury and collagen accumulation. The treatment also led to a decrease in the expression of genes associated with fibrogenesis. To understand the mechanisms behind these effects, the researchers conducted target prediction, molecular docking, and enzyme activity assays. They identified L7DG as a potent inhibitor of protein tyrosine phosphatase 1B (PTP1B), with an IC50 value of 2.10 µM. Further investigations revealed that L7DG inhibited PTP1B activity, which in turn up-regulated AMPK phosphorylation, ultimately inhibiting HSC activation. The findings from this study align with previous research that highlights the role of HSCs in liver fibrosis. For instance, chronic liver injury leads to inflammation and fibrosis through the activation of myofibroblasts, primarily derived from HSCs[2]. Moreover, the regression of liver fibrosis involves the elimination of these activated myofibroblasts and the resorption of the fibrous scar[2]. The study by Fudan University adds to this body of knowledge by demonstrating how L7DG can inhibit HSC activation, thereby offering a potential therapeutic approach. Previous studies have also explored various mechanisms and potential targets for treating liver fibrosis. For example, the inhibition of autophagy regulated by the NF-κB signaling pathway in HSCs has been proposed as a therapeutic approach[3]. Another study identified transcriptional regulators ETS1 and RUNX1 as drivers of HSC plasticity in the context of non-alcoholic steatohepatitis (NASH)-related fibrogenesis[4]. The current study expands on these findings by identifying PTP1B as a new target and demonstrating how its inhibition by L7DG can lead to reduced HSC activation and fibrosis. In summary, the research conducted by Fudan University provides compelling evidence that L7DG could be a promising candidate for the treatment of liver fibrosis. By inhibiting PTP1B and subsequently reducing HSC activation, L7DG offers a novel mechanism to combat this debilitating condition. This study not only contributes to our understanding of liver fibrosis but also opens new avenues for developing effective anti-fibrotic therapies.

MedicineHealthBiochem

References

Main Study

1) Luteolin-7-diglucuronide, a novel PTP1B inhibitor, ameliorates hepatic stellate cell activation and liver fibrosis in mice.

Published 5th August, 2024

https://doi.org/10.1038/s41401-024-01351-3

Related Studies

2) Molecular and cellular mechanisms of liver fibrosis and its regression.

https://doi.org/10.1038/s41575-020-00372-7

3) 3-Methyladenine ameliorates liver fibrosis through autophagy regulated by the NF-κB signaling pathways on hepatic stellate cell.

https://doi.org/10.18632/oncotarget.22539

4) Transcriptional regulation of Hepatic Stellate Cell activation in NASH.

https://doi.org/10.1038/s41598-019-39112-6


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