Pterostilbene Alleviates Cholestasis by Promoting SIRT1 Activity in Hepatocytes and Macrophages

Chuanrui Ma,Jiaqing Xiang,Yaxi Zhao,Guixiao Huang,Zhen Liang,Lin Kang,Guangyan Yang,Kewei Jiang,Shu Yang,Xinyu Wang,Han Wu

doi:10.3389/fphar.2021.785403

Abstract

Background and purpose: FXR is a promising target for the treatment of human cholestatic liver disease (CLD). SIRT1 is a deacetylase which promotes FXR activity through deacetylating FXR. Pterostilbene (PTE) is an activator of SIRT1. However, the role of PTE in cholestasis has so far not been investigated. We examined whether PTE treatment alleviate liver injury in DDC or ANIT-induced experimental cholestasis, and explored the underlying mechanisms. Experimental approach: Mice with DDC- or ANIT-induced cholestasis were treated with different dose of PTE. Primary hepatocytes and bone marrow derived macrophages were used in vitro to assess the molecular mechanism by which PTE may improve CLD. Identical doses of UDCA or PTE were administered to DDC- or ANIT-induced cholestasis mice. Key results: PTE intervention attenuated DDC or ANIT-induced cholestasis. PTE inhibited macrophage infiltration and activation in mouse liver through the SIRT1-p53 signaling pathway, and it improved hepatic bile metabolism through the SIRT1-FXR signaling pathway. Compare with UDCA, the same doses of PTE was more effective in improving cholestatic liver injury caused by DDC or ANIT. Conclusion and implications: SIRT1 activation in macrophages may be an effective CLD treatment avenue. Using CLD models, we thus identified PTE as a novel clinical candidate compound for the treatment of CLD.

Highlights

Genetic and pathophysiological disruptions in bile acid (BA) metabolism and transport lead to altered bile flow and cholestatic liver injury
Treatment of mice with ANIT or feeding 0.1% DDC are commonly accepted methods of establishing sclerosing cholangitis which is similar to primary sclerosing cholangitis (PSC) (Fickert et al, 2007; Fickert et al, 2014); we assessed hepatoprotective effects of PTE using such ANIT or DDC-induced cholestatic liver disease (CLD) models
ANIT treatment increased caspase-3 activity in mouse livers, which was reduced after PTE treatment (Figure 1F)

Summary

Introduction

Genetic and pathophysiological disruptions in bile acid (BA) metabolism and transport lead to altered bile flow and cholestatic liver injury. Current recommended therapies for treating cholestasis mainly rely on the use of ursodeoxycholic acid; such treatment were not proven to be effective in PSC and are ineffective in a proportion of PBC patients (Hirschfield et al, 2010; Eaton et al, 2013). Food and Drug Administration for use in PBC patients, whereas fibrates have yet to be tested in randomized trials (Ghonem et al, 2015). This current limitation regarding therapeutic options emphasizes the urgent need for alternative therapeutic avenues. We examined whether PTE treatment alleviate liver injury in DDC or ANIT-induced experimental cholestasis, and explored the underlying mechanisms. Experimental approach: Mice with DDC- or ANIT-induced cholestasis were treated with different dose of PTE. Identical doses of UDCA or PTE were administered to DDC- or ANIT-induced cholestasis mice

Methods

Results

Discussion

Conclusion