Introduction

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by liver steatosis and inflammation which abnormal immune responses involved in pathogenesis, and there is no approved therapeutic drug. Rhein, one of the main bioactive components of Rheum palmatum, has exerted anti-inflammatory properties. However, the mechanism by which Rhein exerts beneficial effects against NASH is far from elucidated. Here, our study aimed to investigate the therapeutic effects of Rhein on liver steatosis and inflammation and elucidate the related mechanisms of immunoregulation.

Aims & Methods

Male C57BL/6 mice were given high-fat diet for 10 weeks to induce NASH, followed by Rhein suspension administration at a dose of 100mg/kg and 200mg/kg for 4 weeks. The therapeutic effect of NASH was estimated by body weight, liver weight, LW/BW, food intake, the liver appearance and the histological analysis of liver section stained with hematoxylin and eosin. The proportion of lymphocyte cells in the mesenteric lymph nodes (MLNs) was detected by flow cytometry.

Results

Our findings demonstrated that high-fat diet treatment resulted in severe liver inflammation and severe steatosis, while Rhein appreciably reverse these phenomenon, as evidenced by the reduction of body weight, liver wet weight, LW/BW, and liver size in mice. Histological analysis of liver section revealed that administration of Rhein exhibited improvement of severe steatosis, elimination of inflammatory cells and resolution of balloon-like changes when compared to mice in the HFD group. Interestingly, there were no significant differences in food intake among groups of mice, suggesting that the protective effect of Rhein is not achieved by inhibiting appetite. Mechanistically, flow cytometry analysis showed that higher Th1 and Th17 polarized response were detected in the MLN compartments in HFD-induced mice, evidenced by the detection of increased numbers of Th1 cells (CD3+CD4+IFN-γ+) and Th17 cells (CD3+CD4+IL-17+), and Rhein intervention showed significant decrease numbers of Th1 and Th17 in MLNs. In contrast, Rhein treatment significantly increased the numbers of Treg cells (CD3+CD4+Foxp3+) with anti-inflammatory effects in the MLN of NASH mice.

Conclusion

Our results provide novel insights into the protective role of Rhein in modulating the liver steatosis and inflammation, with therapeutic potential for immunology-targeted strategy in the treatment of NASH.

References

[1] Cheng L, Chen Q, Pi R, Chen J. A research update on the therapeutic potential of rhein and its derivatives. Eur J Pharmacol. 2021,899:173908. doi:10.1016/j.ejphar.2021.173908.
[2] Gebru YA, Gupta H, Kim HS, et al. T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease. Int J Mol Sci. 2021,22(22):12190. doi:10.3390/ijms222212190

Disclosure

The authors declare that there are no conflicts of interest regarding the publication of this paper.