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

• Published in: Metabolism, clinical and experimental Vol. 125; p. 154913
• Main Authors: Hana, Claudia A., Tran, Lan V., Mölzer, Christine, Müllner, Elisabeth, Hörmann-Wallner, Marlies, Franzke, Bernhard, Tosevska, Anela, Zöhrer, Patrick A., Doberer, Daniel, Marculescu, Rodrig, Bulmer, Andrew C., Freisling, Heinz, Moazzami, Ali A., Wagner, Karl-Heinz
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2021
• Subjects: Adult; Bilirubin; Bilirubin - blood; Endocrinology and Diabetes; Endokrinologi och diabetes; Female; Gilbert Disease - blood; Gilbert's syndrome; Humans; Ketone bodies; Lipid catabolism; Lipid Metabolism - physiology; Male; Metabolome - physiology; Metabolomics; Middle Aged; Young Adult; Metabolomics; Lipid catabolism; Ketone bodies; Bilirubin; Gilbert's syndrome
• ISSN: 0026-0495; 1532-8600; 1532-8600
• DOI: 10.1016/j.metabol.2021.154913

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. 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. 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. •Mildly hyperbilirubinemic individuals have substantially increased ketone bodies and acetylcarnitine.•Increased AMPK, PPARα and T3 levels are consistent with increased lipid catabolites suggesting enhanced lipid catabolism.•Lipid catabolism partially mediates the favorable blood triglyceride levels of mildly hyperbilirubinemic individuals.•This mechanism seems to be the key strategy in the protective role of bilirubin against chronic metabolic diseases.