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Pank1 plays an important role in coenzyme A homeostasis during fasting
Author(s) -
Leonardi Roberta,
Wang Jina,
Miller Karen,
Rock Charles O.,
Jackowski Suzanne
Publication year - 2009
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.23.1_supplement.520.2
Subject(s) - gluconeogenesis , endocrinology , medicine , knockout mouse , coenzyme a , beta oxidation , cofactor , gene isoform , chemistry , exon , palmitic acid , fatty acid , metabolism , biology , biochemistry , gene , enzyme , reductase
Coenzyme A (CoA) is an essential cofactor synthesized in five steps from pantothenate, and pantothenate kinase (PanK) catalyzes the first and most regulated step. The Pank1 gene encodes two of the four PanK isoforms, PanK1α and 1β. Deletion of exon 3 in the mouse Pank1 gene resulted in loss of expression of both isoforms. The liver of the Pank1 knockout animals contained 40% less total CoA, and the knockout mice showed a blunted response to a pyruvate challenge, indicating impairment in gluconeogenesis. Fasting increases CoA levels to support β‐oxidation and gluconeogenesis. Following a 48h fast, the CoA levels increased by 70% (from 122 ± 4 to 207 ± 23 nmoles/mg of tissue) in livers from wild type and by 50% (from 71 ± 7 to 107 ± 11 nmole/mg of tissue) in livers from knockout mice. Concomitantly, the knockout livers accumulated five times more triglycerides than controls, and the knockout liver homogenates exhibited a decreased rate of palmitic acid oxidation. These results indicate that the reduction in CoA decreases the efficiency of fatty acid β‐oxidation, and that in addition to contributing a large portion of the cofactor pool, Pank1 plays an important role in responding to the increased demand for CoA during fasting. We also observed that the Pank1 knockout males are hyperphagic and 15% heavier than controls, which correlated with a 50% lower malonyl‐CoA in the hypothalamus. Supported by NIH GM062896, CA21765, and ALSAC.