Tanshinone IIA Inhibits the Endoplasmic Reticulum Stress-Induced Unfolded Protein Response by Activating the PPARα/FGF21 Axis to Ameliorate Nonalcoholic Steatohepatitis

Author:

Pi Dajin1,Liang Zheng1,Pan Jinyue1,Zhen Jianwei1,Zheng Chuiyang1,Fan Wen1,Song Qingliang1,Pan Maoxing1,Yang Qinhe1,Zhang Yupei1ORCID

Affiliation:

1. School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China

Abstract

Nonalcoholic steatohepatitis (NASH) is a critical stage in the progression of nonalcoholic fatty liver disease (NAFLD). Tanshinone IIA (TIIA) is a tanshinone extracted from Salvia miltiorrhiza; due to its powerful anti-inflammatory and antioxidant biological activities, it is commonly used for treating cardiovascular and hepatic diseases. A NASH model was established by feeding mice a methionine and choline-deficient (MCD) diet. Liver surface microblood flow scanning, biochemical examination, histopathological examination, cytokine analysis through ELISA, lipidomic analysis, transcriptomic analysis, and Western blot analysis were used to evaluate the therapeutic effect and mechanism of TIIA on NASH. The results showed that TIIA effectively reduced lipid accumulation, fibrosis, and inflammation and alleviated endoplasmic reticulum (ER) stress. Lipidomic analysis revealed that TIIA normalized liver phospholipid metabolism in NASH mice. A KEGG analysis of the transcriptome revealed that TIIA exerted its effect by regulating the PPAR signalling pathway, protein processing in the ER, and the NOD-like receptor signalling pathway. These results suggest that TIIA alleviates NASH by activating the PPARα/FGF21 axis to negatively regulate the ER stress-induced unfolded protein response (UPR).

Funder

the National Nature Science Foundation of China

the Natural Science Foundation of Guangdong Province China

the China Postdoctoral Science Foundation

Fundamental Research Funds for the Central Universities, China

the Traditional Chinese Medicine Bureau of Guangdong Province, China

the Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization

the Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine

Publisher

MDPI AG

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