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.
journal_name
Eur J Pharmacoljournal_title
European journal of pharmacologyauthors
Zhou Z,Deng L,Hu L,Ren Q,Cai Z,Wang B,Li Z,Zhang Ldoi
10.1016/j.ejphar.2020.173300subject
Has Abstractpub_date
2020-09-05 00:00:00pages
173300eissn
0014-2999issn
1879-0712pii
S0014-2999(20)30392-7journal_volume
882pub_type
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