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Research article2021Peer reviewedOpen access

Serum metabolomics analysis reveals increased lipid catabolism in mildly hyperbilirubinemic Gilbert's syndrome individuals

Hana, Claudia A.; Tran, Lan, V; Moelzer, Christine; Muellner, Elisabeth; Hoermann-Wallner, Marlies; Franzke, Bernhard; Tosevska, Anela; Zoehrer, Patrick A.; Doberer, Daniel; Marculescu, Rodrig; Bulmer, Andrew C.; Freisling, Heinz; Moazzami, Ali A.; Wagner, Karl-Heinz

Abstract

Background: The protective role of mildly elevated bilirubin against CVD and diabetes mellitus type 2 (DMT2) is associated with a favorable lipid phenotype. As the mechanistic understanding of this protection in humans remains elusive, we aimed to assess the metabolomics profile of mildly hyperbilirubinemic (Gilbert's syndrome; GS) individuals especially targeting lipid catabolism. Methods and results: Using NMR serum metabolomics of 56 GS individuals and 56 age and gender-matched healthy controls, GS individuals demonstrated significantly greater concentrations of acetylcarnitine (+20%, p < 0.001) and the ketone bodies, 3-hydroxybutyric acid (+132%, p < 0.001), acetoacetic acid (+95%, p < 0.001) and acetone (+46%, p < 0.001). Metabolites associated with an increased mitochondrial lipid metabolism such as citrate (+15%, p < 0.001), anaplerotic amino acid intermediates and creatinine were significantly greater and creatine significantly reduced in GS individuals. Stimulators of lipid catabolism including AMPK (+59%, p < 0.001), pPPAR alpha (+24%, p < 0.001) and T3 (+9%, p = 0.009) supported the metabolomics data while concomitantly blood glucose and insulin (-33%, p = 0.002) levels were significantly reduced. We further showed that the increased lipid catabolism partially mediates the favorable lipid phenotype (lower triglycerides) of GS individuals. Increased trimethylamine (+35%, p < 0.001) indicated changes in trimethylamine metabolism, an emerging predictor of metabolic health. Conclusion: We showed an enhanced lipid catabolism in mildly hyperbilirubinemic individuals, novel evidence as to why these individuals are leaner and protected against chronic metabolic diseases emphasizing bilirubin to be a promising future target in obese and dyslipidemia patients. (c) 2021 Published by Elsevier Inc.

Keywords

Bilirubin; Metabolomics; Lipid catabolism; Ketone bodies; Gilbert's syndrome

Published in

Metabolism
2021, volume: 125, article number: 154913
Publisher: W B SAUNDERS CO-ELSEVIER INC

SLU Authors

Global goals (SDG)

SDG3 Good health and well-being

UKÄ Subject classification

Endocrinology and Diabetes

Publication identifier

  • DOI: https://doi.org/10.1016/j.metabol.2021.154913

Permanent link to this page (URI)

https://res.slu.se/id/publ/114435