T266M variants of ANGPTL4 improve lipid metabolism by modifying their binding affinity to acetyl-CoA carboxylase in obstructive sleep apnea

Angiopoietin-like protein 4 (ANGPTL4) is recognized as a crucial regulator in lipid metabolism. Acetyl-CoA carboxylases (ACACAs) play a role in the β-oxidation of fatty acids. Yet, the functions of ANGPTL4 and ACACA in dyslipidemia of obstructive sleep apnea (OSA) remain unclear. This study included 125 male OSA subjects from the Shanghai Sleep Health Study (SSHS) who were matched for age, body mass index (BMI), and lipid profile. Serum ANGPTL4 levels were measured <i>via</i> ELISA. The ANGPTL4 T266M variants of 4455 subjects along with their anthropometric, fasting biochemical, and standard polysomnographic parameters were collected. Linear regression was used to analyze the associations between quantitative traits and ANGPTL4 T266M. Molecular docking and molecular dynamic simulation were employed to compare the effects of the wild-type ANGPTL4 and its T266M mutation on ACACA. Serum ANGPTL4 levels significantly decreased with increasing OSA severity (non-OSA: 59.6 ± 17.4 ng/mL, mild OSA: 50.0 ± 17.5 ng/mL, moderate OSA: 46.3 ± 15.5 ng/mL, severe OSA: 19.9 ± 14.3 ng/mL, respectively, <i>p</i> = 6.02 × 10⁻¹⁶). No associations were found between T266M and clinical characteristics. Molecular docking indicated that mutant ANGTPL4 T266M had stronger binding affinity for the ACACA protein, compared with wild-type ANGPTL4. In terms of protein secondary structure, mutant ANGTPL4 T266M demonstrated greater stability than wild-type ANGPTL4. Serum ANGTPL4 levels were significantly decreased in OSA patients, particularly among individuals with severe OSA. Although functional ANGTPL4 T266M variants were not associated with lipid levels in OSA, ANGTPL4 T266M could enhance binding affinity for the ACACA protein, potentially regulating lipid metabolism.

血管生成素样蛋白4（Angiopoietin-like protein 4, ANGPTL4）被认为是脂质代谢的关键调控因子。乙酰辅酶A羧化酶家族（Acetyl-CoA carboxylases, ACACAs）参与脂肪酸β氧化过程。然而，ANGPTL4与ACACA在阻塞性睡眠呼吸暂停（obstructive sleep apnea, OSA）所致血脂异常中的功能尚不明确。本研究纳入了来自上海睡眠健康研究（Shanghai Sleep Health Study, SSHS）的125名男性OSA患者，这些患者在年龄、体重指数（body mass index, BMI）及血脂谱方面进行了匹配。通过酶联免疫吸附测定（ELISA）检测血清ANGPTL4水平。收集了4455名受试者的ANGPTL4 T266M变异位点信息，及其人体测量学指标、空腹生化指标与标准多导睡眠监测参数。采用线性回归分析定量性状与ANGPTL4 T266M之间的关联。通过分子对接与分子动力学模拟，对比野生型ANGPTL4及其T266M突变体对ACACA的作用效果。血清ANGPTL4水平随OSA严重程度升高呈显著下降趋势（非OSA组：59.6±17.4 ng/mL，轻度OSA组：50.0±17.5 ng/mL，中度OSA组：46.3±15.5 ng/mL，重度OSA组：19.9±14.3 ng/mL，p=6.02×10⁻¹⁶）。未发现T266M变异与临床特征存在关联。分子对接结果显示，相较于野生型ANGPTL4，突变型ANGPTL4 T266M与ACACA蛋白的结合亲和力更强。在蛋白质二级结构层面，突变型ANGPTL4 T266M较野生型展现出更高的稳定性。OSA患者血清ANGPTL4水平显著降低，尤其在重度OSA患者中更为明显。尽管功能性ANGPTL4 T266M变异与OSA患者的血脂水平无显著关联，但ANGPTL4 T266M可增强其与ACACA蛋白的结合亲和力，潜在参与脂质代谢的调控。