The\nRole of Human Adiponectin Receptor 1 in 2‑Ethylhexyl\nDiphenyl Phosphate Induced Lipid Metabolic Disruption

Epidemiological evidence links exposure\nto 2-ethylhexyl diphenyl\nphosphate (EHDPP) with lipid metabolic disruption, typically attributed\nto nuclear receptors, while the role of membrane receptors remains\nunderexplored. This study explored the role of adiponectin receptor\n1 (AdipoR1) in EHDPP-induced lipid metabolic disturbances. We examined\nEHDPP’s binding affinity and transcriptional impact on AdipoR1.\nAdipoR1 knockdown (AdipoR1<sup>kd</sup>) human liver cells and coculture\nexperiments with AdipoR1 activator (AdipoRon) were used to investigate\nthe effect and the mechanism. EHDPP disrupted triglyceride and phospholipid\nsynthesis and altered corresponding gene expression, mirroring effects\nin AdipoR1<sup>kd</sup> cells but diminishing in EHDPP-treated AdipoR1<sup>kd</sup> cells. RNA sequencing revealed that EHDPP primarily disrupted\noxidative phosphorylation and insulin signaling dependent on AdipoR1.\nMechanistically, EHDPP interacted with AdipoR1 and reduced AdipoR1\nprotein levels at 10<sup>–7</sup> mol/L or higher, weakening\nthe activation of the calmodulin dependent protein kinase β\n(CaMKKβ)/AMPK/acetyl CoA carboxylase pathway. Furthermore, EHDPP\npretreatment blocked the increase in Ca<sup>2+</sup> flux and the\ncorresponding kinase CaMKKβ, as well as liver kinase B1 (LKB1)\nactivation induced by AdipoRon, which is necessary for AMPK activation.\nCollectively, these findings demonstrate that EHDPP-induced lipid\nimbalance is partially dependent on AdipoR1, expanding the understanding\nof environmental metabolic disruptors beyond nuclear receptors.