TY - JOUR
T1 - Developmental regulation and localization of carnitine palmitoyltransferases (CPTs) in rat brain
AU - Jernberg, Jennifer N.
AU - Bowman, Caitlyn E.
AU - Wolfgang, Michael J.
AU - Scafidi, Susanna
N1 - Funding Information:
This work was supported in part by a National Institutes of Health grant K08NS069815 to S.S. and R01NS072241 to M.J.W. C.E.B. was supported in part by a fellowship from the American Heart Association 15PRE25090309. The authors thank Yana Sandlers, Ph.D. (Hugo W. Moser Research Institute at Kennedy Krieger) for acyl-CoA quantification and analysis. The authors have no conflicts of interest to declare. All experiments were conducted in compliance with the ARRIVE guidelines.
Publisher Copyright:
© 2017 International Society for Neurochemistry
PY - 2017/8/1
Y1 - 2017/8/1
N2 - While the brain's high energy demands are largely met by glucose, brain is also equipped with the ability to oxidize fatty acids for energy and metabolism. The brain expresses the carnitine palmitoyltransferases (CPTs) that mediate carnitine-dependent entry of long-chain acyl-CoAs into the mitochondrial matrix for β-oxidation – CPT1a and CPT2 located on the outer and inner mitochondrial membranes, respectively. Their developmental profile, regional distribution and activity as well as cell type expression remain unknown. We determined that brain CPT1a RNA and total protein expression were unchanged throughout post-natal development (PND0, PND7, PND14, PND21 and PND50); however, CPT2 RNA peaked at PND 21 and remained unchanged through PND50 in all regions studied (cortex, hippocampus, midbrain, and cerebellum). Both long-chain acyl CoA dehydrogenase and medium acyl-CoA dehydrogenase showed a similar developmental profile to CPT2. Acylcarnitines, generated as a result of CPT1a activity, significantly increased with age and peaked at PND21 in all brain regions, concurrent with the increased expression of enzymes involved in mitochondrial β-oxidation. The CPT system is highly enriched in vivo in hippocampus and cerebellum, relative to cortex and midbrain, and is exclusively present in astrocytes and neural progenitor cells, while absent in neurons, microglia, and oligodendrocytes. Using radiolabeled oleate, we demonstrate regional differences in brain fatty acid oxidation that may be blocked by the irreversible CPT1a inhibitor etomoxir. This study contributes to the field of knowledge in brain cell-specific metabolic pathways, which are important for understanding normal brain development and aging, as well as pathophysiology of neurological diseases. Read the Editorial Comment for this article on page 347. (Figure presented.).
AB - While the brain's high energy demands are largely met by glucose, brain is also equipped with the ability to oxidize fatty acids for energy and metabolism. The brain expresses the carnitine palmitoyltransferases (CPTs) that mediate carnitine-dependent entry of long-chain acyl-CoAs into the mitochondrial matrix for β-oxidation – CPT1a and CPT2 located on the outer and inner mitochondrial membranes, respectively. Their developmental profile, regional distribution and activity as well as cell type expression remain unknown. We determined that brain CPT1a RNA and total protein expression were unchanged throughout post-natal development (PND0, PND7, PND14, PND21 and PND50); however, CPT2 RNA peaked at PND 21 and remained unchanged through PND50 in all regions studied (cortex, hippocampus, midbrain, and cerebellum). Both long-chain acyl CoA dehydrogenase and medium acyl-CoA dehydrogenase showed a similar developmental profile to CPT2. Acylcarnitines, generated as a result of CPT1a activity, significantly increased with age and peaked at PND21 in all brain regions, concurrent with the increased expression of enzymes involved in mitochondrial β-oxidation. The CPT system is highly enriched in vivo in hippocampus and cerebellum, relative to cortex and midbrain, and is exclusively present in astrocytes and neural progenitor cells, while absent in neurons, microglia, and oligodendrocytes. Using radiolabeled oleate, we demonstrate regional differences in brain fatty acid oxidation that may be blocked by the irreversible CPT1a inhibitor etomoxir. This study contributes to the field of knowledge in brain cell-specific metabolic pathways, which are important for understanding normal brain development and aging, as well as pathophysiology of neurological diseases. Read the Editorial Comment for this article on page 347. (Figure presented.).
KW - Carnitine palmitoyltransferase
KW - development
KW - fatty acid oxidation
KW - mitochondria
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U2 - 10.1111/jnc.14072
DO - 10.1111/jnc.14072
M3 - Article
C2 - 28512781
AN - SCOPUS:85023201751
SN - 0022-3042
VL - 142
SP - 407
EP - 419
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 3
ER -