New insights into salvianolic acid A action: Regulation of the TXNIP/NLRP3 and TXNIP/ChREBP pathways ameliorates HFD-induced NAFLD in rats.

Chunchun Ding,Dongyan Gao,Ning Zhang,Xiaofeng Tian,Jihong Yao,Guo Zu,Yan Zhao,Xue Shi,Zhenlu Li,Li Lv,Junjun Zhou

doi:10.1038/srep28734

Abstract

Salvianolic acid A (SalA), one of the most efficacious polyphenol compounds extracted from Radix Salvia miltiorrhiza (Danshen), has been shown to possess many potential pharmacological activities. This study aimed to investigate whether SalA has hepatoprotective effects against high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and to further explore the mechanism underlying this process. SalA treatment significantly attenuated HFD-induced obesity and liver injury, and markedly decreased lipid accumulation in HFD-fed rat livers. Moreover, SalA treatment ameliorated HFD-induced hepatic inflammation and oxidative stress by decreasing hepatotoxic levels of cytokines, suppressing the overproduction of reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA) and preventing the decreased expression of superoxide dismutase (SOD). Importantly, SalA reversed the HFD- or palmitic acid (PA)-induced activation of the NLRP3 inflammasome, the nuclear translocation of ChREBP and the up-regulation of FAS, and these effects were accompanied by TXNIP down-regulation. However, TXNIP siRNA treatment partially abrogated the above-mentioned effects of SalA in PA-treated HepG2 cells. Together, our results demonstrated, for the first time, that SalA protects against HFD-induced NAFLD by ameliorating hepatic lipid accumulation and inflammation, and these protective effects may partially due to regulation of the TXNIP/NLRP3 and TXNIP/ChREBP pathways.

Highlights

Salvia miltiorrhiza Bunge (Danshen/Red sage, SM), a well-known traditional herbal medicine, has been widely used in China for centuries
We investigated the role of Thioredoxin-interacting protein (TXNIP) in high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD), and we explored whether Salvianolic acid A (SalA) down-regulates TXNIP expression during NAFLD and whether TXNIP inhibition activates protective mechanisms by inhibiting NLRP3 inflammasome activation and Carbohydrate response element-binding protein (ChREBP) nuclear translocation
The pathogenic process of NAFLD is strongly linked to overnutrition; lipid accumulation, oxidative stress and inflammation have been widely suggested to play a pivotal role in the transition from steatosis to NASH2,5

Summary

Introduction

Salvia miltiorrhiza Bunge (Danshen/Red sage, SM), a well-known traditional herbal medicine, has been widely used in China for centuries. Recent studies by our group and others have shown that salvianolic acid B (SalB) and several other polyphenols can protect against NAFLD17–20 Despite these observations, whether SalA has a hepatoprotective effects against HFD-induced NAFLD and the underlying molecular mechanism remain unclear. Recent studies have shown that TXNIP in turn modulates ChREBP activity, resulting in the regulation of other ChREBP target genes that play important roles in glucose and lipid metabolism[36]. Whether this cross talk mechanism between TXNIP and ChREBP contributes to the development of HFD-induced NAFLD remains unknown. Our findings provide new insights into the mechanisms underlying the pharmacological effects of SalA on NAFLD, and we expect that these findings will contribute to novel strategies for the management of NAFLD

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Conclusion