Serum metabolomics analysis reveals increased lipid catabolism in mildly hyperbilirubinemic Gilbert's syndrome individuals
Claudia A Hana, Lan V Tran, Christine Mölzer, Elisabeth Müllner, Marlies Hörmann-Wallner, Bernhard Franzke, Anela Tosevska, Patrick A Zöhrer, Daniel Doberer, Rodrig Marculescu, Andrew C Bulmer, Heinz Freisling, Ali A Moazzami, Karl-Heinz Wagner, Claudia A Hana, Lan V Tran, Christine Mölzer, Elisabeth Müllner, Marlies Hörmann-Wallner, Bernhard Franzke, Anela Tosevska, Patrick A Zöhrer, Daniel Doberer, Rodrig Marculescu, Andrew C Bulmer, Heinz Freisling, Ali A Moazzami, Karl-Heinz Wagner
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), pPPARα (+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.
Keywords: Bilirubin; Gilbert's syndrome; Ketone bodies; Lipid catabolism; Metabolomics.
Conflict of interest statement
Declaration of competing interest None, the authors have declared that no conflict of interest exists.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Source: PubMed