Fenofibrate anti-RARα/RXRα dimerization to attenuate all-trans retinoic acid-induced hyperlipidemia and hepatic steatosis in mice.

All-trans retinoic acid (ATRA), the active metabolite of vitamin A, serves as the first-line therapy for acute promyelocytic leukemia (APL) in clinical. However, increasing clinical evidence indicates that ATRA treatment is frequently associated with dyslipidemia, the underlying molecular mechanisms of which remain unclear. Fenofibrate, a specific agonist of peroxisome proliferator-activated receptor alpha (PPARα), is widely used in the management of metabolic disorders, yet its potential to alleviate ATRA-induced lipid abnormalities has not been fully elucidated. In this study, we established a mouse model of ATRA-induced hyperlipidemia and hepatic steatosis to investigate the underlying mechanisms and assess the therapeutic effects of fenofibrate as a combinatorial agent. Our findings revealed that ATRA promoted the formation of RARα/RXRα heterodimers, which activated the hepatic FOXO1-APOCIII pathway, leading to hyperlipidemia and hepatic lipid accumulation in mice. Fenofibrate effectively counteracted these effects by activating PPARα, thereby competitively inhibiting RARα binding to RXRα and restoring lipid homeostasis. This study reveals a novel mechanism underlying ATRA-induced hyperlipidemia and hepatic lipid accumulation, which offers a theoretical foundation for the clinical use of fenofibrate in managing ATRA-induced hyperlipidemia and hepatic steatosis.