VLDL-Specific Increases of Fatty Acids in Autism Spectrum Disorders Correlates with Social Interaction

Abnormalities of lipid metabolism contribute to ASD pathogenesis has been argued, but the mechanisms are not fully understood. We characterized the lipids metabolism in ASD children by lipidomics, and identified the dramatic alterations of 71 metabolites involved in lipid biosynthesis and metabolism, oxidative stress, and synaptic function. Identified fatty acids (FAs) indicated the correlations with clinical social interaction score of ASD diagnosis as well as lipoproteins-triglyceride concentrations in ASD. We also found the specific reduction of very-low-density lipoprotein (VLDL) in ASD, which showing correlations with a decrease of APOB concentrations in ASD. We further found a significant increase in APOJ known as a sensor for oxidative stress, demonstrating enhancing oxidative stress in ASD is due to VLDL-specific dyslipidemia. These results demonstrate the increases in FAs are due to VLDL-specific degradation, providing novel insights to uncover the mechanisms such as oxidative stress generations via mitochondrial dysfunction underlying ASD pathology. Funding Statement: This work was supported by the Strategic Research Program for Brain Sciences from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to H.M.; the Grant-in-Aid for Scientific Research on Innovative Areas (#21200014) from MEXT to H.M.; SENSHIN Medical Research Foundation to H.M. and N.U.; Hamamatsu Foundation for Science and Technology Promotion to H.M.; the Grant-in-Aid for Early-Career Scientists (18K14814) from the Japan Society for the Promotion of Science (JSPS) to N.U.; Takeda Science Foundation to H.M. and N.U.; The Osaka Medical Research Foundation for Intractable Diseases to N.U.; Research Grant for Public Health Science to N.U.; Eli Lilly Japan Research Grant to N.U.; the Grant for Life Cycle Medicine from Faculty of Medical Sciences, University of Fukui to N.U. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All procedures were approved by the Ethics Committee of the University of Fukui and the Hamamatsu University School of Medicine, and were conducted in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects of the Ministry of Health, Labour and Welfare of Japan. All participants were given a complete description of the study and provided written informed consent from their parent and/or legal guardian before enrolled.