1. Academic Validation
  2. Hepatoprotective effects of ZLY16, a dual peroxisome proliferator-activated receptor α/δ agonist, in rodent model of nonalcoholic steatohepatitis

Hepatoprotective effects of ZLY16, a dual peroxisome proliferator-activated receptor α/δ agonist, in rodent model of nonalcoholic steatohepatitis

  • Eur J Pharmacol. 2020 Sep 5;882:173300. doi: 10.1016/j.ejphar.2020.173300.
Zongtao Zhou 1 Liming Deng 1 Lijun Hu 1 Qiang Ren 1 Zongyu Cai 1 Bin Wang 1 Zheng Li 2 Luyong Zhang 3
Affiliations

Affiliations

  • 1 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
  • 2 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China. Electronic address: li.zheng.sky@163.com.
  • 3 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: lyzhang@cpu.edu.cn.
Abstract

Nonalcoholic fatty liver disease (NAFLD), a chronic progressive liver disease, covers a series of liver damage encompassing steatosis, nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. However, there are no approved therapies for NAFLD. Herein, we characterize the pharmacological profile of ZLY16 ((E)-2-(4-(3-(2,3-dihydrobenzo[b]thiophen -5-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid), a novel highly potent PPARα/δ agonist with relative higher potency on PPARγ. The chronic effects of ZLY16 on NASH development were evaluated in MCD-induced db/db mice. ZLY16 revealed decreased liver injury biomarkers, hepatic steatosis, inflammation, ballooning, and oxidative stress. Further mechanism researches suggested that ZLY16 inhibited liver inflammation and fibrosis by regulating gene expression including COLIA1, TIMP, TGFβ, TNFα, and IL6. Moreover, ZLY16 offers more favorable effects in decreasing liver TC and TG accumulation, blocking liver fibrosis and inflammation than GFT505, the most advanced candidate of PPARα/δ agonist for the treatment of NASH. These results indicate that ZLY16 is a highly potent PPARα/δ agonist that provides great protection against NASH development, and may be useful for the treatment of NAFLD/NASH.

Keywords

Fatty liver; Fibrosis; Inflammation; PPAR.

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