Qu Fei, Wang Yuming, Zhang Yanping, Chen Feng, Ai Yuanliang, Wen Weibo, Liao Jiabao, Li Hanzhou, Pei Huan, Lu Mingxi, Yang Ling, Wang Ning, Cui Huantian
Jiaxing Hospital of Traditional Chinese Medicine Jiaxing China.
Tianjin University of Traditional Chinese Medicine Tianjin China.
Food Sci Nutr. 2025 Mar 5;13(3):e70086. doi: 10.1002/fsn3.70086. eCollection 2025 Mar.
Non-alcoholic steatohepatitis (NASH) poses a serious threat to human health. Alisol B 23-Acetate (AB23A) has shown beneficial effects on NASH, but its mechanism of action remains unclear. We conducted in vitro experiments by inducing L02 cell damage with free fatty acids (FFA) and administering various concentrations of AB23A. We found that AB23A intervention reduced triglyceride (TG) levels in FFA-induced L02 cells and improved cellular steatosis. Transcriptomic analysis revealed that AB23A intervention significantly downregulated glucose-regulated protein 94 (Grp94), indicating that AB23A primarily regulates the protein processing pathway in the endoplasmic reticulum. Within this pathway, AB23A intervention also significantly downregulated endoplasmic reticulum stress (ERS)-related genes (, , ) and ER-associated degradation (ERAD)-related genes (, , ). When we silenced GRP94, the regulatory effects of AB23A on TG levels, cellular steatosis, ERS-related proteins (p-PERK/PERK, p-eIF2α/eIF2α, ATF4), and ERAD-related proteins (FBXO2, DERL, HSP90α) disappeared. In vivo, AB23A intervention promoted recovery of the liver index in NASH mice, reduced hepatic inflammatory infiltration and lipid deposition, improved serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, and reduced liver TG levels. RT-qPCR and Western blot results demonstrated that AB23A intervention dose-dependently downregulated the gene and protein expression of GRP94 and ERS- and ERAD-related factors. There was no significant difference between the effects of high-dose AB23A intervention and PPC intervention. This study demonstrated, through both in vitro and in vivo experiments, that AB23A improves hepatic steatosis. This effect may be related to the downregulation of GRP94, which suppresses ERS and ERAD, thereby restoring ER homeostasis.
非酒精性脂肪性肝炎（NASH）对人类健康构成严重威胁。泽泻醇B 23-乙酸酯（AB23A）已显示出对NASH有益的作用，但其作用机制仍不清楚。我们通过用游离脂肪酸（FFA）诱导L02细胞损伤并给予不同浓度的AB23A进行了体外实验。我们发现AB23A干预降低了FFA诱导的L02细胞中的甘油三酯（TG）水平，并改善了细胞脂肪变性。转录组分析显示，AB23A干预显著下调了葡萄糖调节蛋白94（Grp94），表明AB23A主要调节内质网中的蛋白质加工途径。在该途径中，AB23A干预还显著下调了内质网应激（ERS）相关基因（……）和内质网相关降解（ERAD）相关基因（……）。当我们沉默GRP94时，AB23A对TG水平、细胞脂肪变性、ERS相关蛋白（p-PERK/PERK、p-eIF2α/eIF2α、ATF4）和ERAD相关蛋白（FBXO2、DERL、HSP90α）的调节作用消失。在体内，AB23A干预促进了NASH小鼠肝脏指数的恢复，减少了肝脏炎症浸润和脂质沉积，改善了血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）活性，并降低了肝脏TG水平。RT-qPCR和蛋白质印迹结果表明，AB23A干预剂量依赖性地下调了GRP94以及ERS和ERAD相关因子的基因和蛋白表达。高剂量AB23A干预与PPC干预的效果之间没有显著差异。这项研究通过体外和体内实验均证明，AB23A改善了肝脂肪变性。这种作用可能与GRP94的下调有关，GRP94抑制了ERS和ERAD，从而恢复了内质网稳态。
