The anti-fibrotic efficacy of adelmidrol depends on hepatic PPAR gamma levels

作者全名："Xiang, Huanyu; Xiao, Jing; Sun, Zilin; Liu, Zongyi; Zhang, Junhao; Xiang, Hongyan; Ren, Hong; Hu, Peng; Peng, Mingli"

作者地址："[Xiang, Huanyu; Xiao, Jing; Sun, Zilin; Liu, Zongyi; Zhang, Junhao; Xiang, Hongyan; Ren, Hong; Hu, Peng; Peng, Mingli] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Key Lab Mol Biol Infect Dis,Minist, Chongqing, Peoples R China"

通信作者："Hu, P; Peng, ML (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Key Lab Mol Biol Infect Dis,Minist, Chongqing, Peoples R China."

来源：BIOMEDICINE & PHARMACOTHERAPY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001029008700001

JCR分区：Q1

影响因子：6.9

年份：2023

卷号：165

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Adelmidrol; Liver fibrosis; Hepatic PPAR gamma; Chemical compounds studied in this article: Adelmidrol (Pubchem CID:176874); Specific PPAR gamma antagonist GW9662 (Pubchem CID:644213)

摘要："Adelmidrol, an anti-inflammatory small-molecule compound, can treat inflammatory diseases like arthritis and colitis in a PPAR gamma-dependent manner. Effective anti-inflammatory therapy is beneficial in delaying the progression of liver fibrosis. This study aimed to investigate the effect and underlying mechanisms of adelmidrol on hepatic fibrosis induced by CCl4 and CDAA-HFD. In the CCl4 model, adelmidrol (10 mg/kg) significantly reduced the incidence of liver cirrhosis from 76.5% to 38.9%, with a reduction of ALT, AST, and extracellular matrix deposition. RNA-seq revealed adelmidrol markedly inhibited the activation of hepatic scar-associated Trem2(+) macrophages and PDGFR alpha(+) stellate cells. Adelmidrol exhibited a limited anti-fibrotic effect in CDAA-HFD-induced fibrosis. Further, inconsistencies were observed in the expression trends in liver PPAR gamma in both models. CCl4 injury led to the continuous decrease in hepatic PPAR gamma levels, adelmidrol treatment up-regulated hepatic PPAR gamma expression and down-regulated the expression of pro-inflammatory factor NF-kappa B and pro-fibrotic factor TGF-beta 1. Adelmidrol also inhibited the activation of macrophages and HSCs in a PPAR gamma-dependent manner in vitro. GW9662, a specific PPAR. antagonist, counteracted the anti-fibrotic effect of adelmidrol. In CDAA-HFD-induced model, hepatic PPAR. expression gradually increased with the progress of modeling. Adelmidrol enhanced steatosis in hepatocytes by the activation of the PPAR gamma/CD36 pathway in the CDAA-HFD model and FFA-treated HepG2, showing a limited anti-fibrotic effect. GW9662 reversed the pro-steatotic effect of adelmidrol and improved fibrosis. The anti-fibrotic outcomes of adelmidrol were related to hepatic PPAR. levels, which depends on the synergistic effect of PPAR. agonism caused by adelmidrol on hepatocytes, macrophages, and HSCs in different pathological states."

基金机构："National Administration of Traditional Chinese Medicine; Second Affiliated Hospital of Chongqing Medical University; First batch of key Disciplines on Public Health in Chongqing, Health Commission of Chongqing, China"

基金资助正文："This work was supported by a pilot project of clinical cooperation between traditional Chinese and western medicine for significant and complicated diseases of National Administration of Traditional Chinese Medicine: hepatic fibrosis, Remarkable Innovation-Clinical Research Project, The Second Affiliated Hospital of Chongqing Medical University and The First batch of key Disciplines on Public Health in Chongqing, Health Commission of Chongqing, China."