ZLY032, the first-in-class dual FFA1/PPARδ agonist, improves glucolipid metabolism and alleviates hepatic fibrosis. (September 2020)

• Record Type: Journal Article
• Authors: Li, Zheng; Zhou, Zongtao; Hu, Lijun; Deng, Liming; Ren, Qiang; Zhang, Luyong
• Is Part Of: Pharmacological research. Volume 159(2020)
• Publication Date: 2020-09
• Subjects: ACC1 acetyl-CoA carboxylase 1 -- Acta2 actin alpha 2 -- 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 -- BAT brown adipose tissue -- Col1a1 collagen type I alpha 1 -- CPT1α carnitine palmitoyl transferase 1α -- FAS fatty acid synthetase -- FFA1 free fatty acid receptor 1 -- FOXO1 Forkhead box protein O1 -- HbA1c glycosylated hemoglobin -- HDL high-density lipoprotein -- INSR insulin receptor -- IRS-1 insulin receptor substrate 1 -- IRS-2 insulin receptor substrate 2 -- ITT insulin tolerance test -- LCAD Long-chain specific acyl-CoA dehydrogenase -- LDL low-density lipoprotein -- LPL Lipoprotein lipase -- MCD methionine choline-deficient -- NAFLD non-alcoholic fatty liver disease -- NASH nonalcoholic steatohepatitis -- OGTT oral glucose tolerance test -- PCNA proliferating cell nuclear antigen -- PDX-1 pancreas duodenum homeobox-1 -- PI3K (p85α) phosphoinositide 3-kinase regulatory subunit p85α -- PPAR peroxisome proliferator-activated receptor -- ROS reactive oxygen species -- RT-PCR reverse transcription-polymerase chain reaction -- SCD1 stearoyl-CoA desaturase 1 -- α-SMA alpha smooth muscle actin -- SREBP-1c sterol regulatory element-binding protein 1c -- T2DM type 2 diabetes mellitus -- Tgfβ transforming growth factor-β -- Timp-1 tissue inhibitor of metalloproteinases-1 -- TNFα tumor necrosis factor α -- WAT white adipose tissue; Fatty liver -- FFA1 -- Fibrosis -- PPAR -- Type 2 diabetes; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.105035
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Chronic treatment with ZLY032, the first-in-class dual FFA1/PPARδ agonist, revealed greater benefits on glucolipid metabolism and fatty liver than TAK-875, the most advanced candidate of FFA1 agonists. Moreover, ZLY032 prevented CCl4 -induced liver fibrosis by reducing the expressions of genes involved in inflammation and fibrosis development. Highlights: ZLY032 improved glucolipid metabolism and fatty liver in ob/ob mice and NASH model. ZLY032 exhibited better insulin sensitivity and lipid improvement than TAK-875. ZLY032 improved pancreatic β-cell function of ob/ob mice. ZLY032 prevented MCD diet-induced or CCl4 -induced liver fibrosis. ZLY032 regulates genes related to lipid metabolism, inflammation, fibrosis, oxidative stress and mitochondrial function. Abstract: The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptor δ (PPARδ) are considered as anti-diabetic targets based on their role in improving insulin secretion and resistance. Based on their synergetic mechanisms, we have previously identified the first-in-class dual FFA1/PPARδ agonist ZLY032. After long-term treatment, ZLY032 significantly improved glucolipid metabolism and alleviated fatty liver in ob/ob mice and methionine choline-deficient diet-fed db/db mice, mainly by regulating triglyceride metabolism, fatty acid β-oxidation, lipid synthesis, inflammation, oxidative stress and mitochondrial function. Notably, ZLY032 exhibited greater advantages on lipid metabolism, insulin sensitivity and pancreatic β-cell function than TAK-875, the most advanced candidate of FFA1 agonists. Moreover, ZLY032 prevented CCl4 -induced liver fibrosis by reducing the expressions of genes involved in inflammation and fibrosis development. These results suggest that the dual FFA1/PPARδ agonists such as ZLY032 may be useful for the treatment of metabolic disorders.