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.
Keywords:
FFA1; Fatty liver; Fibrosis; PPAR; Type 2 diabetes.
Copyright © 2020 Elsevier Ltd. All rights reserved.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzofurans / pharmacology
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Blood Glucose / drug effects*
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Blood Glucose / metabolism
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Chemical and Drug Induced Liver Injury / genetics
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Chemical and Drug Induced Liver Injury / metabolism
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Chemical and Drug Induced Liver Injury / pathology
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Chemical and Drug Induced Liver Injury / prevention & control*
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Gene Expression Regulation
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Insulin Resistance*
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Insulin-Secreting Cells / drug effects
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Insulin-Secreting Cells / metabolism
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Lipid Metabolism / drug effects*
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Lipids / blood
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Liver / drug effects*
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Liver / metabolism
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Liver / pathology
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Liver Cirrhosis, Experimental / genetics
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Liver Cirrhosis, Experimental / metabolism
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Liver Cirrhosis, Experimental / pathology
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Liver Cirrhosis, Experimental / prevention & control*
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Male
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Mice, Inbred C57BL
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Non-alcoholic Fatty Liver Disease / drug therapy*
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Non-alcoholic Fatty Liver Disease / genetics
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Non-alcoholic Fatty Liver Disease / metabolism
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Non-alcoholic Fatty Liver Disease / pathology
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Receptors, Cytoplasmic and Nuclear / agonists*
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, G-Protein-Coupled / agonists*
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Receptors, G-Protein-Coupled / metabolism
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Signal Transduction
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Sulfones / pharmacology
Substances
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Benzofurans
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Blood Glucose
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Ffar1 protein, mouse
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Lipids
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Ppard protein, mouse
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Receptors, Cytoplasmic and Nuclear
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Receptors, G-Protein-Coupled
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Sulfones
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TAK-875