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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #319808
Title: Unique plasma metabolomic signatures of individuals with inherited disorders of long-chain fatty acid oxidation

Author
item MCCOIN, COLLIN - University Of California
item PICCOLO, BRIAN - Arkansas Children'S Nutrition Research Center (ACNC)
item KNOTTS, TINA - University Of California
item MATERN, D - University Of California
item VOCKLEY, J - University Of California
item GILLINGHAM, M - University Of California

Submitted to: Journal of Inherited Metabolic Disease
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/22/2016
Publication Date: 2/23/2016
Citation: Mccoin, C.S., Piccolo, B.D., Knotts, T.A., Matern, D., Vockley, J., Gillingham, M.B. 2016. Unique plasma metabolomic signatures of individuals with inherited disorders of long-chain fatty acid oxidation. Journal of Inherited Metabolic Disease. 39(3):399-408.

Interpretive Summary: Blood and urine acylcarnitine metabolite profiles are commonly used to diagnose long-chain fatty acid oxidation disorders, which are rare inborn genetic conditions in which fat cannot be readily burned for energy in the tissues. The global metabolic impact of long-chain FAOD has not been reported. We utilized untargeted metabolomics (analysis of hundreds of small molecule metabolites all at once, with interpretation of biochemical pathways that are altered) to characterize plasma metabolites in 12 overnight-fasted individuals with FAOD (10 LCHAD, 2 CPT2) and 11 healthy age-, sex-, and body mass index (BMI)-matched controls. 832 metabolites were identified in plasma, and multivariate statistical analysis identified 168 non-acylcarnitine variables that discriminated FAOD subjects and controls. FAOD individuals had significantly higher triglycerides and lower specific phosphatidylethanolamines, ceramides and sphingomyelins. Differences in phosphatidylcholines were also found but the directionality differed by species. Further, there were differences in several non-lipid metabolites including '-tocopherol, citric acid and isocitric acid. This analysis provides evidence that LCHAD/CPT2 deficiency, even in asymptomatic clinically-controlled individuals, significantly alters complex lipid pathway flux. This metabolic signature may provide powerful clinical tools capable of distinguishing FAOD sub-types and disease severity, or provide clues regarding the etiology of FAOD symptoms. The metabolite patterns that are altered under these conditions of poor fat metabolism can also be very informative to understand differences in fat metabolism across the population as a whole.

Technical Abstract: Blood and urine acylcarnitine profiles are commonly used to diagnose long-chain fatty acid oxidation disorders (FAOD: i.e., long-chain hydroxy-acyl-CoA dehydrogenase [LCHAD] and carnitine palmitoyltransferase 2 [CPT2] deficiency), but the global metabolic impact of long-chain FAOD has not been reported. We utilized untargeted metabolomics to characterize plasma metabolites in 12 overnight-fasted individuals with FAOD (10 LCHAD, 2 CPT2) and 11 healthy age-, sex-, and body mass index (BMI)-matched controls. 832 metabolites were identified in plasma, and partial least squared-discriminant analysis (PLS-DA) identified 168 non-acylcarnitine variables that discriminated FAOD subjects and controls. FAOD individuals had significantly higher triglycerides and lower specific phosphatidylethanolamines, ceramides and sphingomyelins. Differences in phosphatidylcholines were also found but the directionality differed by species. Further, there were differences in several non-lipid metabolites including gamma-tocopherol, citric acid and isocitric acid. This analysis provides evidence that LCHAD/CPT2 deficiency, even in asymptomatic clinically-controlled individuals, significantly alters complex lipid pathway flux. This metabolic signature may provide powerful clinical tools capable of distinguishing FAOD sub-types and disease severity, or provide clues regarding the etiology of FAOD symptoms.