A novel FFA1 agonist, CPU025, improves glucose-lipid metabolism and alleviates fatty liver in obese-diabetic (ob/ob) mice. (March 2020)

• Record Type: Journal Article
• Authors: Li, Zheng; Liu, Chunxia; Zhou, Zongtao; Hu, Lijun; Deng, Liming; Ren, Qiang; Qian, Hai
• Is Part Of: Pharmacological research. Volume 153(2020)
• Publication Date: 2020-03
• Subjects: ACC1 acetyl-CoA carboxylase 1 -- ALT Alanine aminotransferase -- ANGPTL3 angiopoietin-like 3 -- Apo C-II apolipoprotein C-II -- Apo C-III apolipoprotein C-III -- AST Aspartate transaminase -- ATGL adipose triglyceride lipase -- AUC area under curve -- CHO Chinese hamster ovary -- CKMB creatine kinase-MB -- CPT1α carnitine palmitoyl transferase 1α -- FAS fatty acid synthetase -- FFA1 free fatty acid receptor 1 -- FLIPR fluorometric imaging plate reader -- GLP-1 glucagon-like peptide 1 -- HbA1c glycosylated hemoglobin -- HDL high-density lipoprotein -- HRP horseradish peroxidase -- LCAD Long-chain specific acyl-CoA dehydrogenase -- LDL low-density lipoprotein -- LPL Lipoprotein lipase -- OGTT oral glucose tolerance test -- PPAR peroxisome proliferator-activated receptor -- PVDF polyvinylidene fluoride -- ROS reactive oxygen species -- RT-PCR reverse transcription-polymerase chain reaction -- SAR structure-activity relationship -- SCD1 stearoyl-CoA desaturase 1 -- SREBP-1c sterol regulatory element-binding protein 1c -- T2DM type 2 diabetes mellitus; Diabetes -- Fatty liver -- FFA1 -- Nsulin secretion -- PPAR; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.104679
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: The in vitro, in vivo and modeling studies of CPU025 were explored in this study. Chronic treatment with CPU025 revealed greater benefits on glycemic control, lipid profiles and fatty liver in ob/ob mice than TAK-875, the most advanced candidate of FFA1 agonists. Highlights: CPU025 revealed dual agonistic activities on FFA1 and PPAR δ . CPU025 exhibited better glycemic control and lipid improvement than TAK-875. CPU025 improved β-cell function with dense arrangement of insulin-positive cells. CPU025 significantly reduced the vesicular steatosis and ballooning in liver. CPU025 alleviates fatty liver by multiple mechanisms. Abstract: In the effort to identify anti-diabetic drug, we discovered a novel free fatty acid receptor 1 (FFA1) agonist CPU025, which is structurally different from previously reported FFA1 agonists. The present study revealed CPU025 is a potent FFA1 agonist (EC50 = 38.7 nM) with moderate agonistic activity on PPAR δ (EC50 = 625.6 nM), and promotes insulin secretion at a glucose-dependent manner. Modeling study also illuminated CPU025 forms interaction with key residues closely related to the agonistic effects of FFA1 and PPAR δ . Long-term treatment of CPU025 exerted better glycemic control and lipid profile than TAK-875, the most advanced FFA1 partial agonist in this field. Moreover, CPU025 improved β-cell function and alleviated fatty liver in ob/ob mice. Further study suggested CPU025 could alleviate fatty liver through regulating the expression of genes involved in fatty acid β-oxidation, lipoprotein lipolysis, lipid synthesis, oxidative stress and mitochondrial function. These results indicate that long-term treatment of CPU025 improves glucose and lipid metabolism, and may be useful for the treatment of diabetes mellitus and fatty liver.