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 in ANGPTL8, 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, ANGPTL8 expression can be upregulated by insulin stimulation, indicating it as an insulin-responsive hormone regulating dyslipidemia in OSA. Mechanistically, SNP rs3745683 attenuated ANGPTL8 transcription by inhibiting its binding to transcription factor YBX1. Insulin prompted AKT1 to phosphorylate YBX1 at Ser102, facilitating YBX1’s nuclear translocation and subsequent regulation of ANGPTL8 expression and lipid synthesis. Specific knockdown of YBX1 in mouse liver confirmed its necessity for ANGPTL8 expression and hepatic lipid synthesis in vivo. Our findings highlight ANGPTL8 as a critical regulator of dyslipidemia in OSA patients, offering a promising therapeutic avenue for managing metabolic syndrome in OSA.

The authors have declared no competing interest.

ChiCTR1900025714

This study was also supported by grants-in-aid from Ministry of Science and Technology of the People' s Republic of China (2021ZD0201900), National Natural Science Foundation of China (81971240, 82070824, 82171125, 81970869, 81970870, 82271153, 82000967, 82101205, 82100105, 82301291, 82300962), Shanghai Municipal Commission of Science and Technology (Grant No.18DZ2260200), the Interdisciplinary Program of Shanghai Jiao Tong University (YG2023LC11), Youth Innovation Promotion Association of CAS (2023289), Shanghai Sailing Program grant (23YF1431900). The funding sources had no role in design, conduct, analysed, and interpreted of this study.

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