Sinapic Acid Reduces Oxidative Stress and Pyroptosis via Inhibition of BRD4 in Alcoholic Liver Disease.

Junyi Chu,Ruimin Sun,Xiaohui Kang,Musen Lin,Jihong Yao,Wen Shan,Ning Zhang,Yan Hu,Zhecheng Wang,Yan Zhao,Sai Wang,Guoyang Li,Ran Yan

doi:10.3389/fphar.2021.668708

Abstract

Alcoholic liver disease (ALD) is one of the main causes of death in chronic liver disease. Oxidative stress and pyroptosis are important factors leading to ALD. Bromodomain-containing protein 4 (BRD4) is a factor that we have confirmed to regulate ALD. As a phenolic acid compound, sinapic acid (SA) has significant effects in antioxidant, anti-inflammatory and liver protection. In this study, we explored whether SA regulates oxidative stress and pyroptosis through BRD4 to play a protective effect in ALD. Male C57BL/6 mice and AML-12 cells were used for experiments. We found that SA treatment largely abolished the up-regulation of BRD4 and key proteins of the canonical pyroptosis signalling in the liver of mice fed with alcohol, while conversely enhanced the antioxidant response. Consistantly, both SA pretreatment and BRD4 knockdown inhibited oxidative stress, pyroptosis, and liver cell damage in vitro. More importantly, the expression levels of BRD4 and pyroptosis indicators increased significantly in ALD patients. Molecule docking analysis revealed a potent binding of SA with BRD4. In conclusion, this study demonstrates that SA reduces ALD through BRD4, which is a valuable lead compound that prevents the ALD process.

Highlights

Long-term and excessive alcohol consumption can lead to progressive steatohepatitis and fibrosis, which further develops into liver cirrhosis and hepatocellular carcinoma
The morphological and histological examination showed that the liver sizes were enlarged, the colour changed, lipid droplet accumulated in hepatocytes in the model group
The current study presents the first attempt to demonstrate that sinapic acid (SA) contributes to the protection against Alcoholic liver disease (ALD) by reducing Bromodomaincontaining protein 4 (BRD4)

Summary

Introduction

Long-term and excessive alcohol consumption can lead to progressive steatohepatitis and fibrosis, which further develops into liver cirrhosis and hepatocellular carcinoma. Alcohol-induced liver steatosis is initially manifested as the accumulation of small or large droplets in hepatocytes (Gao and Bataller, 2011). When alcohol continues to be overloaded, it will further aggravate liver damage, leading to inflammation, oxidative stress, and multiple pathways of programmed cell death (Rangwala et al, 2011; Ikura and Caldwell, 2015; Ma et al, 2020). Due to the complicated pathogenesis of alcohol-associated liver disease (ALD) and unclear underlying mechanism, is still there is no targeted treatment. It is necessary to better understand the pathogenesis of ALD and develop new and safe drugs for the treatment

Methods

Results

Conclusion