Liver‐Derived Ketogenesis via Overexpressing HMGCS2 Promotes the Recovery of Spinal Cord Injury

Abstract The liver is the major ketogenic organ of the body, and ketones are reported to possess favorable neuroprotective effects. This study aims to elucidate whether ketone bodies generated from the liver play a critical role in bridging the liver and spinal cord. Mice model with a contusive spinal cord injury (SCI) surgery is established, and SCI induces significant histological changes in mice liver. mRNA‐seq of liver tissue shows the temporal changes of ketone bodies‐related genes, β‐hydroxybutyrate dehydrogenase (BDH1) and solute carrier family 16 (monocarboxylic acid transporters), member 6 (SLC16A6). Then, an activated ketogenesis model is created with adult C57BL/6 mice receiving the tail intravenous injection of GPAAV8‐TBG‐Mouse‐Hmgcs2‐CMV‐ mCherry ‐WPRE (HMGCS2 liver ) and mice receiving equal AAV8‐Null being the control group (Vector liver ). Then, the mice undergo either a contusive SCI or sham surgery. The results show that overexpression of HMG‐CoA synthase (Hmgcs2) in mice liver dramatically alleviates SCI‐mediated pathological changes and promotes ketogenesis in the liver. Amazingly, liver‐derived ketogenesis evidently alleviates neuron apoptosis and inflammatory microglia activation and improves the recovery of motor function of SCI mice. In conclusion, a liver‐spinal cord axis can be bridged via ketone bodies, and enhancing the production of the ketone body within the liver has neuroprotective effects on traumatic SCI.