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

doi:10.1016/j.metabol.2021.154913

Abstract

BackgroundThe 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 resultsUsing 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. ConclusionWe 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.

Highlights

Diabetes mellitus type 2 (DMT2) and cardiovascular diseases (CVD) are reaching epidemic proportions worldwide, affecting all socioeconomic backgrounds and ethnicities [1,2,3]
In the present study we explored the relationship between activated PPARα and AMPK with their downstream metabolites AC and ketone bodies (KB) and found significant correlations reflecting the stimulatory role of PPARα and AMPK in lipid catabolism, both increased in GS individuals (Fig. 4)
The GS-associated metabolites as well PPARα, AMPK, insulin, glucagon and THs reveal a complementary pattern of lipid catabolic conditions in GS individuals. These findings suggest for the first time underlying mechanisms based on PPARα, AMPK, insulin and THs associated with an increased lipid catabolism in mildly hyperbilirubinemic subjects

Summary

Introduction

Diabetes mellitus type 2 (DMT2) and cardiovascular diseases (CVD) are reaching epidemic proportions worldwide, affecting all socioeconomic backgrounds and ethnicities [1,2,3]. A vast body of evidence indicates that mildly elevated circulating bilirubin is a protective factor against obesity, high blood lipids and insulin resistance [6,7,8,9,10,11,12] and is inversely associated with the risk of DMT2 and CVD [13,14,15,16]. The protective role of mildly elevated bilirubin against CVD and diabetes mellitus type 2 (DMT2) is associated with a favorable lipid phenotype. 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

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Conclusion