Systemic metabolite profiling reveals sexual dimorphism of AIBP control of metabolism in mice

• Published in: PloS one Vol. 16; no. 4; p. e0248964
• Main Authors: Kim, Jun-Dae, Zhu, Lingping, Sun, Quan, Fang, Longhou
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-04-2021; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Bile; Bile acids; Binding proteins; Biology and Life Sciences; Biosynthesis; Cholesterol; Cholesterol - metabolism; Dimorphism (Biology); Editing; Engineering and Technology; Fatty acids; Female; Females; Geriatrics; Glyceraldehyde-3-phosphate dehydrogenase; Health aspects; High density lipoprotein; Homeostasis; Lipid Metabolism; Lipids; Localization; Low density lipoprotein; Male; Medical research; Medicine; Medicine and Health Sciences; Metabolic disorders; Metabolism; Metabolites; Metabolome; Mice; Mice, Inbred C57BL; Mice, Knockout; NAD; NAD - metabolism; Phosphoproteins - metabolism; Physiological aspects; Plasma; Polyunsaturated fatty acids; Principal components analysis; Racemases and Epimerases - metabolism; Regeneration; Research and Analysis Methods; Rodents; Sex differences; Sex Factors; Sexual dimorphism; Sterols; Tocopherol; Vitamin E; Vitamins; United States; United States > US; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0248964

Emerging studies indicate that APOA-I binding protein (AIBP) is a secreted protein and functions extracellularly to promote cellular cholesterol efflux, thereby disrupting lipid rafts on the plasma membrane. AIBP is also present in the mitochondria and acts as an epimerase, facilitating the repair of dysfunctional hydrated NAD(P)H, known as NAD(P)H(X). Importantly, AIBP deficiency contributes to lethal neurometabolic disorder, reminiscent of the Leigh syndrome in humans. Whereas cyclic NADPHX production is proposed to be the underlying cause, we hypothesize that an unbiased metabolic profiling may: 1) reveal new clues for the lethality, e.g., changes of mitochondrial metabolites., and 2) identify metabolites associated with new AIBP functions. To this end, we performed unbiased and profound metabolic studies of plasma obtained from adult AIBP knockout mice and control littermates of both genders. Our systemic metabolite profiling, encompassing 9 super pathways, identified a total of 640 compounds. Our studies demonstrate a surprising sexual dimorphism of metabolites affected by AIBP deletion, with more statistically significant changes in the AIBP knockout female vs male when compared with the corresponding controls. AIBP knockout trends to reduce cholesterol but increase the bile acid precursor 7-HOCA in female but not male. Complex lipids, phospholipids, sphingomyelin and plasmalogens were reduced, while monoacylglycerol, fatty acids and the lipid soluble vitamins E and carotene diol were elevated in AIBP knockout female but not male. NAD metabolites were not significantly different in AIBP knockout vs control mice but differed for male vs female mice. Metabolites associated with glycolysis and the Krebs cycle were unchanged by AIBP knockout. Importantly, polyamine spermidine, critical for many cellular functions including cerebral cortex synapses, was reduced in male but not female AIBP knockout. This is the first report of a systemic metabolite profile of plasma samples from AIBP knockout mice, and provides a metabolic basis for future studies of AIBP regulation of cellular metabolism and the pathophysiological presentation of AIBP deficiency in patients.