British journal of pharmacology · 2026
Dual pharmacological targeting of coactivator-associated arginine methyltransferase 1 (CARM1) and salt inducible kinase (SIK) drives ketogenesis in both hepatocytes and mice.
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Bergonci Tábata, Rosenbæk Troels Kjær, Windross Samuel J, Keiding Ulrik B, Pinilla Estéfano, Stuckert Katrine P, Hansen Jakob, Nielsen Camilla B, Gomes Jemila Peter, Davies Lucy R, Palmfeldt Johan, Loeschcke Volker, Andersen Charlotte U, Simonsen Ulf, Poulsen Thomas B, Johannsen Mogens
Аннотация
BACKGROUND AND PURPOSE: Ketone bodies are liver-derived circulating energy metabolites that positively impact most hallmarks of ageing. Ketone bodies increase during calorie restriction and fasting, two of the more widely perceived methods to increase health span. Adhering to a strict diet to increase ketogenesis is demanding, which leaves a significant unmet need for a pharmacological alternative. The present study hypothesised that chemical genetic screening can reveal novel proteins that will regulate ketogenesis.
EXPERIMENTAL APPROACH: We developed phenotypic screening assays to determine ketone bodies in hepatocytes. We applied two libraries of annotated small molecule compounds to determine proteins regulating ketogenesis. Adenosine 3',5' cyclic monophosphate (cAMP) measurements, quantitative reverse transcription polymerase chain reaction (RT-qPCR), western blotting and small interfering RNA (siRNA) silencing were performed to validate targets in hepatocytes. RT-qPCR and proteomics were performed to validate targets in liver tissues. Drosophila melanogaster was used in a longevity assay. Mice were used to demonstrate regulation of ketogenesis in vivo.
KEY RESULTS: Ketogenesis links pathways involved in metabolic health and longevity, identifying coactivator-associated arginine methyltransferase 1 (CARM1) as a novel regulator. Joint pharmacological targeting of CARM1 and salt inducible kinases (SIK) synergise, resulting in high ketogenic induction in hepatocytes. Finally, we demonstrate the dual activation of ketogenesis with homeostatic blood-glucose in non-fasting mice.
CONCLUSION AND IMPLICATIONS: Ketogenesis represents a promising biomarker and therapeutic target for metabolic interventions targeting age-related diseases. Our data suggest that CARM1 and SIKs warrant further investigation for pharmacological induction of ketogenesis, with potential clinical applications in ageing-associated metabolic dysfunction.
EXPERIMENTAL APPROACH: We developed phenotypic screening assays to determine ketone bodies in hepatocytes. We applied two libraries of annotated small molecule compounds to determine proteins regulating ketogenesis. Adenosine 3',5' cyclic monophosphate (cAMP) measurements, quantitative reverse transcription polymerase chain reaction (RT-qPCR), western blotting and small interfering RNA (siRNA) silencing were performed to validate targets in hepatocytes. RT-qPCR and proteomics were performed to validate targets in liver tissues. Drosophila melanogaster was used in a longevity assay. Mice were used to demonstrate regulation of ketogenesis in vivo.
KEY RESULTS: Ketogenesis links pathways involved in metabolic health and longevity, identifying coactivator-associated arginine methyltransferase 1 (CARM1) as a novel regulator. Joint pharmacological targeting of CARM1 and salt inducible kinases (SIK) synergise, resulting in high ketogenic induction in hepatocytes. Finally, we demonstrate the dual activation of ketogenesis with homeostatic blood-glucose in non-fasting mice.
CONCLUSION AND IMPLICATIONS: Ketogenesis represents a promising biomarker and therapeutic target for metabolic interventions targeting age-related diseases. Our data suggest that CARM1 and SIKs warrant further investigation for pharmacological induction of ketogenesis, with potential clinical applications in ageing-associated metabolic dysfunction.