Insulin-AKT1-YBX1 Regulation of ANGPTL8 Promote Lipogenesis in Obstructive Sleep Apnea-Associated Dyslipidemia

Abstract

Dyslipidemia is a hallmark of obstructive sleep apnea (OSA)-induced metabolic syndrome, yet the mechanisms remain poorly understood. We conducted a genome-wide association study on lipid traits in the OSA cohorts, identifying the SNP rs3745683 inANGPTL8, significantly associated with reductions in multiple lipid traits. ANGPTL8, an essential lipogenic hormone and potential therapeutic target for metabolic syndrome, showed elevated expression in OSA patients compared to healthy controls, strongly correlated with increased insulin levels. Notably,ANGPTL8expression can be upregulated by insulin stimulation, indicating it as an insulin-responsive hormone regulating dyslipidemia in OSA. Mechanistically, SNP rs3745683 attenuatedANGPTL8transcription by inhibiting its binding to transcription factor YBX1. Insulin prompted AKT1 to phosphorylate YBX1 at Ser102, facilitating YBX1’s nuclear translocation and subsequent regulation ofANGPTL8expression and lipid synthesis. Specific knockdown of YBX1 in mouse liver confirmed its necessity forANGPTL8expression and hepatic lipid synthesis in vivo. Our findings highlightANGPTL8as a critical regulator of dyslipidemia in OSA patients, offering a promising therapeutic avenue for managing metabolic syndrome in OSA.