Traumatic brain injury alters hepatic gluconeogenic metabolism assessed using hyperpolarized pyruvate
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Background
Acute phase response is an early immunometabolic response to brain injuries, primarily coordinated by the liver via the activation of acute phase proteins. These immune responses can be both beneficial, promoting tissue repair, and detrimental, exacerbating neurological deficits, if not properly controlled. Despite the central role of the liver in immunometabolism, how hepatic metabolism dynamically adapts to traumatic brain injury remains under explored, primarily due to limited liver-specific modalities that can assess metabolic pathways in vivo . 13 C MRI utilizing hyperpolarized 13 C-pyruvate can assess key regulatory enzyme activities in hepatic metabolism.
Methods
Rats with controlled cortical impact were studied in vivo using hyperpolarized [1- 13 C]pyruvate and [2- 13 C]pyruvate under fed and fasted conditions 3-4 days after injury. Hyperpolarized 13 C products, including [ 13 C]bicarbonate from [1- 13 C]pyruvate and [5- 13 C]glutamate, [1- 13 C]acetyl-L-carnitine, and [2- 13 C]phosphoenolpyruvate from [2- 13 C]pyruvate, were evaluated to assess mitochondrial and gluconeogenic metabolism. In parallel, liver tissues were collected following [U- 13 C 3 ]pyruvate injection for NMR isotopomer analysis of phosphoenolpyruvate, glucose, and glutamate.
Results
While no metabolic differences were detected under fed condition, [ 13 C]bicarbonate and [2- 13 C]phosphoenolpyruvate increased after brain injury under fasted condition, indicating an upregulation of the hepatic gluconeogenic pathway after injury. 13 C NMR of liver tissue extracts from injured rats showed an elevated [2,3- 13 C 2 ]glutamate-to-[4,5- 13 C 2 ]glutamate ratio and increased 13 C-labeling in phosphoenolpyruvate than controls, confirming enhanced hepatic gluconeogenic pathway.
Conclusion
This study demonstrates that hepatic acute phase response to brain injuries can be monitored in vivo by hyperpolarized pyruvate, which may be further utilized for longitudinal immunometabolic evaluation of the liver during pathogenesis and therapeutic interventions.
