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- Title
HWL‐088, a new and highly effective FFA1/PPARδ dual agonist, attenuates nonalcoholic steatohepatitis by regulating lipid metabolism, inflammation and fibrosis.
- Authors
Hu, Lijun; Zhou, Zongtao; Deng, Liming; Ren, Qiang; Cai, Zongyu; Wang, Bin; Li, Zheng; Wang, Guangji
- 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.
- Subjects
PEROXISOME proliferator-activated receptors; LIPID metabolism; LIPOLYSIS; FATTY liver; FIBROSIS; PATHOLOGY; FREE fatty acids; INFLAMMATION
- Publication
Journal of Pharmacy & Pharmacology, 2020, Vol 72, Issue 11, p1564
- ISSN
0022-3573
- Publication type
Article
- DOI
10.1111/jphp.13342