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The Importance of Being CoA: Generation of a Pank1 Knockout Mouse with Reduced CoA Levels
Author(s) -
Leonardi Roberta,
Jackson Pamela,
Wang Jina,
Charles O. Rock,
Jackowski Suzanne
Publication year - 2008
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.22.1_supplement.643.8
Subject(s) - knockout mouse , ketone bodies , coenzyme a , gluconeogenesis , medicine , endocrinology , cofactor , beta oxidation , metabolism , gene knockout , biology , gene isoform , chemistry , biochemistry , gene , enzyme , reductase
Coenzyme A (CoA) is an essential cofactor involved in energy metabolism. CoA is assembled in five steps from pantothenate, and pantothenate kinase (PanK) catalyzes the first and most regulated step. Mammals possess four PanK isoforms, PanK1α, 1β, 2 and 3, encoded by three separate genes. The murine PanK1α and 1 arise from alternate transcriptional start sites of the Pank1 gene, and their transcript levels are particularly abundant in liver, kidney and heart. We derived a Pank1 knockout mouse to investigate the effect on CoA and the physiological consequences. The Pank1 knockout mice were viable and fertile, but their livers contained 40% less CoA, and the hearts of knockout males, but not females, showed a 60% decrease in the cofactor level. CoA is required for gluconeogenesis and ketone body production during fasting. The steady state glucose and ketone body levels after a 48 h fast were comparable to wild type, but knockout mice showed a blunted response to a pyruvate challenge. Serum triglycerides were higher, and Pank1 knockout mice were 10–15% larger than wild type controls. These results indicate that a 40–60% reduction in CoA is not lethal but impairs the ability of the liver to quickly produce glucose from pyruvate. The higher serum triglycerides and weight of the knockout animals suggest that the reduction in CoA decreases the efficiency of fatty acid β‐oxidation. Supported by NIHGM062896 and ALSAC.