Novel Dual PPAR\nδ/γ Partial Agonist Induces\nHepatic Lipid Accumulation through Direct Binding and Inhibition of\nAKT1 Phosphorylation, Mediating CD36 Upregulation

ZLY06\nis a dual agonist of peroxisome proliferator-activated receptor\n(PPAR) δ/γ, showing potential therapeutic effects on metabolic\nsyndrome. However, our research has revealed that ZLY06 exhibits hepatotoxicity\nin normal C57BL/6J mice, though the precise mechanism remains unclear.\nThis study aims to investigate the manifestations and mechanisms of\nZLY06-induced hepatotoxicity. We administered ZLY06 via oral gavage\nto C57BL/6J mice (once daily for six weeks) and monitored various\nindicators to preliminarily explore its hepatotoxicity. Additionally,\nwe further investigate the specific mechanisms of ZLY06-induced hepatotoxicity\nusing PPAR inhibitors (GW9662 and GSK0660) and the Protein kinase\nB (AKT) activator (SC79). Results showed that ZLY06 led to increased\nserum ALP, ALT and AST, as well as elevated liver index and hepatic\nlipid levels. There was upregulation in the gene and protein expression\nof lipid metabolism-related molecules <i>Acc</i>, <i>Scd1</i>, <i>Cd36</i>, <i>Fabp1</i> and <i>Fabp2</i> in hepatocytes, with <i>Cd36</i> showing\nthe most significant change. Furthermore, cotreatment with SC79 significantly\nreduced ZLY06-induced hepatotoxicity in AML12 cells, evidenced by\ndecreased intracellular TG levels and downregulation of CD36 expression.\nSpecific knockdown of CD36 also mitigated ZLY06-induced hepatotoxicity.\nThe study found that ZLY06 may bind to AKT1, inhibiting its phosphorylation\nactivation, with the downregulation of p-AKT1 preceding the upregulation\nof CD36. In summary, ZLY06 mediates the upregulation of CD36 by potentially\nbinding to and inhibiting the phosphorylation of AKT1, leading to\nhepatic lipid metabolism disorder and inducing liver toxicity.