Ketogenesis mitigates metabolic dysfunction-associated steatotic liver disease through mechanisms that extend beyond fat oxidation.

Summary

Human isotope flux studies and mouse genetics show that maintaining ketogenesis mitigates liver injury in MASLD/MASH through mechanisms not explained by total fat oxidation alone. HMGCS2 loss induces a MASLD/MASH-like phenotype, whereas BDH1 loss impairs oxidation without worsening injury, indicating ketone-related protective signaling.

Key Findings

• In humans with MASH, liver injury correlates with ketogenesis and total fat oxidation, but not TCA cycle turnover.
• Hepatic HMGCS2 disruption impairs fat oxidation and induces a MASLD/MASH-like phenotype in mice.
• BDH1 disruption reduces fat oxidation without exacerbating steatotic liver injury.
• Overall hepatic fat oxidation is not the primary determinant of MASLD-to-MASH progression; ketogenesis confers protection via additional mechanisms.

Clinical Implications

Therapies that enhance or preserve hepatic ketogenesis (dietary, pharmacological) may reduce liver injury risk in MASLD/MASH; biomarkers of ketone flux could refine patient stratification.

Limitations

• Human data are correlative; interventional validation of enhanced ketogenesis is needed.
• Generalisability across etiologies and comorbidities and long-term outcomes were not assessed.

Future Directions

Test ketogenesis-enhancing interventions (diet, pharmacology) in MASLD/MASH patients; delineate ketone-mediated signaling pathways conferring hepatoprotection.