β-hydroxybutyrate serves as a regulator in ketone body metabolism through lysine β-hydroxybutyrylation.

Summary

β-hydroxybutyrate increases lysine β-hydroxybutyrylation of OXCT1 (at K421), enhancing its activity and promoting ketone utilization during fasting, thereby maintaining metabolic homeostasis. SIRT1 and CBP act as putative Kbhb deacylase and transferase for OXCT1, respectively, revealing a signaling role of β-HB in ketone metabolism.

Key Findings

• β-HB correlates with increased Kbhb of OXCT1 and HMGCS2 in vivo during fasting and in vitro, decreasing after refeeding.
• Kbhb at OXCT1 K421 enhances enzymatic activity; mutation at the site reduces activity, whereas HMGCS2 activity was unaffected.
• SIRT1 and CBP were identified as candidate deacylase and transferase for OXCT1 Kbhb in vitro and in vivo.

Clinical Implications

While preclinical, the findings suggest targets (OXCT1 Kbhb, SIRT1/CBP axis) to modulate ketone handling in conditions such as fasting adaptation, ketogenic diets, diabetes, and ketosis-prone states.

Limitations

• Preclinical models; human tissue validation and clinical relevance remain to be established
• Global Kbhb dynamics across organs and pathologies not comprehensively mapped

Future Directions

Validate OXCT1 Kbhb in human tissues, define SIRT1/CBP regulatory circuitry, and test pharmacologic modulation of Kbhb in metabolic disease models.