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Anaplerosis from heptanoate ‐a propionyl‐CoA precursor‐ in mouse brain
Author(s) -
Wang Xiao,
Allen Frederick,
Sayre Carolyn,
Wan Dinah,
Minkler Paul E.,
Hoppel Charles L.,
Brunengraber Henri
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a340
Subject(s) - pyruvate carboxylase , chemistry , isotopomers , metabolism , beta oxidation , ketone bodies , biochemistry , medicine , endocrinology , enzyme , biology , organic chemistry , molecule
Dietary therapy with triheptanoin, a precursor of anaplerotic propionyl‐CoA, is used for the chronic treatment of long‐chain fatty acid oxidation disorders (Roe, JCI 110 : , 2002) and pyruvate carboxylase deficiency (Mochel, Mol Gen Metab 84 : , 2005). Heptanoate is partially converted in liver to C 5 ‐ketone bodies (β‐ketopentanoate and β‐hydroxypentanoate. These are precursors of propionyl‐CoA in peripheral tissues. We tested whether heptanoate can be taken up as such by the brain. Anesthetized mice were infused with [5,6,7‐ 13 C 3 ]heptanoate (20 to 100 nmol/g x min) for 30 min before freezing the brains. We assayed the concentration and mass isotopomer distribution of brain acyl‐CoAs by LC‐MS‐MS. We found that the brain concentrations of [5,6,7‐ 13 C 3 ]heptanoyl‐CoA, [3,4,5‐ 13 C 3 ]pentanoyl‐CoA, and [1,2,3‐ 13 C 3 ]propionyl‐CoA increased with the rate of infusion of [5,6,7‐ 13 C 3 ]heptanoate. The spectrum of triply‐labeled acyl‐CoAs demonstrates that heptanoate is taken up as such by the brain, and that it is anaplerotic in this organ. Our data support the hypothesis, presented in ( Mol Gen Metab 84 : , 2005) that the neurological status of a patient with pyruvate carboxylase deficiency was improved by anaplerosis from heptanoate in the brain. These investigations are extended to mice deficient in very long‐chain acyl‐CoA dehydrogenase deficiency. Supported by NIH grant DK069752.