Novel aromatic amide Pan-PPAR agonists for dual amelioration of hepatic steatosis and islet dysfunction by promoting cholesterol efflux in the KKAy diabetic mice.

Cholesterol metabolism disorders are a major contributor to type 2 diabetes mellitus (T2DM). Cholesterol accumulation in the liver exacerbates insulin resistance, while cholesterol overload in the pancreatic islets impairs insulin secretion. Peroxisome proliferator activated receptors (PPARs) are considered potential therapeutic targets for cholesterol regulation. Herein, we report a series of novel aromatic amide derivatives as pan-PPAR agonists. Among them, compound 15a exhibited potent and well balanced pan-PPAR agonistic activity and significantly upregulated the expression of ATP binding cassette transporter A1 (ABCA1), a PPAR target gene involved in cholesterol efflux. In a high fat and high sucrose diet induced KKAy diabetic mouse model, 15a markedly reduced plasma cholesterol levels, hepatic cholesterol accumulation, and islet cholesterol deposition. It also demonstrated favorable regulation of glucolipid metabolism, leading to pronounced alleviation of hepatic steatosis and islet dysfunction, while avoiding the weight gain and adiposity side effects associated with PPARγ agonists. SPR experiments demonstrated that 15a interacts with the ligand binding domains (LBDs) of all three PPAR subtypes. Molecular docking and single point mutation assays of key residues confirmed that 15a likely exerts its pan PPAR agonist activity by stabilizing helix 3 of the three PPAR subtypes. Furthermore, 15a exhibits improved pharmacokinetic properties and a favorable safety profile compared to the lead compound. In summary, this study demonstrates that compound 15a significantly ameliorates hepatic steatosis and islet dysfunction associated with T2DM by regulating cholesterol metabolism disorders along the liver-islet axis, highlighting its strong potential for treating hepatic lipid accumulation and T2DM related islet dysfunction.