Affiliation:
1. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
2. Key Laboratory of New Drug Discovery and Evaluation, Guangdong Pharmaceutical University, Guangzhou, China
3. State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
Abstract
Abstract
Objectives
Nonalcoholic fatty liver (NAFLD), a chronic progressive liver disease, is highly correlated with pathoglycemia, dyslipidemia and oxidative stress. The free fatty acid receptor 1 (FFA1) agonists have been reported to improve liver steatosis and fibrosis, and the peroxisome proliferator-activated receptor δ (PPARδ) plays a synergistic role with FFA1 in energy metabolism and fibrosis. HWL-088, a PPARδ/FFA1 dual agonist, exerts better glucose-lowering effects than the representative FFA1 agonist TAK-875. However, the ability of HWL-088 to protect NAFLD was unknown. This study aimed to discover a new strategy for the treatment of NAFLD.
Methods
The methionine- and choline-deficient diet (MCD)-induced Nonalcoholic steatohepatitis (NASH) model was constructed to evaluate the effects of HWL-088.
Key findings
Administration of HWL-088 exerted multiple benefits on glucose control, lipid metabolism and fatty liver. Further mechanism research indicated that HWL-088 promotes lipid metabolism by decreasing lipogenesis and increasing lipolysis. Moreover, HWL-088 attenuates NASH by regulating the expression levels of genes related to inflammation, fibrosis and oxidative stress.
Conclusions
These positive results indicated that PPARδ/FFA1 dual agonist HWL-088 might be a potential candidate to improve multiple pathogenesis of NASH.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Guangdong Province, China
Guangdong Basic and Applied Basic Research Foundation
Key Field R&D Plan Project of Guangdong Province
the Innovative strong school project of Guangdong Pharmaceutical University
the projects of Guangzhou key laboratory of construction and application of new drug screening model systems
Key Laboratory of New Drug Discovery and Evaluation of ordinary universities of Guangdong province
the Innovation Team Projects in Universities of Guangdong Province
Publisher
Oxford University Press (OUP)
Subject
Pharmaceutical Science,Pharmacology
Cited by
3 articles.
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