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 CCl-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.
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http://dx.doi.org/10.1016/j.phrs.2020.105035 | DOI Listing |
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