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

Abstract

Background

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.

Methods

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 via 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.

Results

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, p = 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.

Conclusions

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.

Keywords:

• Angiopoietin-like protein 4
• obstructive sleep apnea
• T266M, ACACA
• molecular docking
• molecular dynamic simulation

Acknowledgements

The authors would like to thank all the subjects for their participation and acknowledge the skillful work of the entire medical staff.

Ethics approval and consent to participate

The ethics committee of Shanghai Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine approved this study according to Helsinki Declaration II. Written consent was provided from each participant before taking part in the study. The trial was registered in the China Clinical Trials Registry (serial number ChiCTR1900025714). The ethical approval number was 2019-KY-050(K).

Authors contributions

Designed study and contributed to data interpretation: XL, HX, XW; collected clinical data and contributed to acquisition of genetic data: XL, WX, ZW, HS, CL, KW, JG, HY, SY; performed data analyses and wrote the manuscript: XL and CL; reviewed/edited the manuscript HX, HZ, XW and SY.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability and materials statement

All data during this study can provide if needed.

Additional information

Funding

This work was supported by the Ministry of Science and Technology of the People’s Republic of China (STI2030-Major Projects2021ZD0201900), National Natural Science Foundation of China (82000967, 82271153); Shanghai Municipal Commission of Science and Technology (Grant No.18DZ2260200); Natural Science Foundation of Shanghai (22ZR1447200); Shanghai Sixth People’s Hospital (ynts202103, ZY (2021-2023)-0205-04); Medical Research Projects of Xuhui District (SHXH202003, SHXH202102).