VLDL-specific increases of fatty acids in autism spectrum disorder correlate with social interaction
Noriyoshi Usui,
Keiko Iwata,
Taishi Miyachi,
Shu Takagai,
Keisuke Wakusawa,
Takahiro Nara,
Kenji J. Tsuchiya,
Kaori Matsumoto,
Daisuke Kurita,
Yosuke Kameno,
Tomoyasu Wakuda,
Kiyokazu Takebayashi,
Yasuhide Iwata,
Toru Fujioka,
Takaharu Hirai,
Manabu Toyoshima,
Tetsuo Ohnishi,
Tomoko Toyota,
Motoko Maekawa,
Takeo Yoshikawa,
Masato Maekawa,
Kazuhiko Nakamura,
Masatsugu Tsujii,
Toshiro Sugiyama,
Norio Mori,
Hideo Matsuzaki
Affiliations
Noriyoshi Usui
Research Center for Child Mental Development, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan; Department of Child Development, United Graduate School of Child Development, Osaka University, Osaka 565−0871, Japan; Life Science Innovation Center, University of Fukui, Fukui 910-1193, Japan; Center for Medical Research and Education, and Department of Neuroscience and Cell Biology, Graduate School of Medicine, Osaka University, Osaka 565−0871, Japan; Department of Neuroscience and Cell Biology, Graduate School of Medicine, Osaka University, Osaka 565−0871, Japan; Global Center for Medical Engineering and Informatics, Osaka University, Osaka 565−0871, Japan; Addiction Research Unit, Osaka Psychiatric Research Center, Osaka Psychiatric Medical Center, Osaka 541-8567, Japan
Keiko Iwata
Research Center for Child Mental Development, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan; Department of Child Development, United Graduate School of Child Development, Osaka University, Osaka 565−0871, Japan; Life Science Innovation Center, University of Fukui, Fukui 910-1193, Japan
Taishi Miyachi
Department of Pediatrics, Nagoya City University Medical School, Aichi 467-8601, Japan
Shu Takagai
Department of Child and Adolescent Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan
Keisuke Wakusawa
Department of Rehabilitation, Miyagi Children's Hospital, Miyagi 989-3126, Japan
Takahiro Nara
Department of Rehabilitation, Miyagi Children's Hospital, Miyagi 989-3126, Japan
Kenji J. Tsuchiya
Research Center for Child Mental Development, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan
Kaori Matsumoto
Graduate School of Psychology, Kanazawa Institute of Technology, Ishikawa 921-8054, Japan
Daisuke Kurita
Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan
Yosuke Kameno
Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan
Tomoyasu Wakuda
Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan
Kiyokazu Takebayashi
Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan
Yasuhide Iwata
Department of Psychiatry and Neurology, Fukude Nishi Hospital, Shizuoka 437-1216, Japan
Toru Fujioka
Research Center for Child Mental Development, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan; Department of Child Development, United Graduate School of Child Development, Osaka University, Osaka 565−0871, Japan
Takaharu Hirai
Department of Child Development, United Graduate School of Child Development, Osaka University, Osaka 565−0871, Japan; Department of Community Health Nursing, School of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
Manabu Toyoshima
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama 351−0198, Japan
Tetsuo Ohnishi
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama 351−0198, Japan
Tomoko Toyota
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama 351−0198, Japan
Motoko Maekawa
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama 351−0198, Japan
Takeo Yoshikawa
Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama 351−0198, Japan
Masato Maekawa
Department of Laboratory Medicine, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan
Kazuhiko Nakamura
Department of Psychiatry, Hirosaki University School of Medicine, Aomori 036-8562, Japan
Masatsugu Tsujii
School of Contemporary Sociology, Chukyo University, Aichi 470−0393, Japan
Toshiro Sugiyama
Research Center for Child Mental Development, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan
Norio Mori
Department of Psychiatry and Neurology, Fukude Nishi Hospital, Shizuoka 437-1216, Japan
Hideo Matsuzaki
Research Center for Child Mental Development, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan; Department of Child Development, United Graduate School of Child Development, Osaka University, Osaka 565−0871, Japan; Life Science Innovation Center, University of Fukui, Fukui 910-1193, Japan; Corresponding author at: Research Center for Child Mental Development, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan.
Background: Abnormalities of lipid metabolism contributing to the autism spectrum disorder (ASD) pathogenesis have been suggested, but the mechanisms are not fully understood. We aimed to characterize the lipid metabolism in ASD and to explore a biomarker for clinical evaluation. Methods: An age-matched case-control study was designed. Lipidomics was conducted using the plasma samples from 30 children with ASD compared to 30 typical developmental control (TD) children. Large-scale lipoprotein analyses were also conducted using the serum samples from 152 children with ASD compared to 122 TD children. Data comparing ASD to TD subjects were evaluated using univariate (Mann-Whitney test) and multivariate analyses (conditional logistic regression analysis) for main analyses using cofounders (diagnosis, sex, age, height, weight, and BMI), Spearman rank correlation coefficient, and discriminant analyses. Findings: Forty-eight significant metabolites involved in lipid biosynthesis and metabolism, oxidative stress, and synaptic function were identified in the plasma of ASD children by lipidomics. Among these, increased fatty acids (FAs), such as omega-3 (n-3) and omega-6 (n-6), showed correlations with clinical social interaction score and ASD diagnosis. Specific reductions of very-low-density lipoprotein (VLDL) and apoprotein B (APOB) in serum of ASD children also were found by large-scale lipoprotein analysis. VLDL-specific reduction in ASD was correlated with APOB, indicating VLDL-specific dyslipidaemia associated with APOB in ASD children. Interpretation: Our results demonstrated that the increases in FAs correlated positively with social interaction are due to VLDL-specific degradation, providing novel insights into the lipid metabolism underlying ASD pathophysiology. Funding: This study was supported mainly by MEXT, Japan.
