Pantothenate kinase 1 is required to support the metabolic transition from the fed to the fasted state
Coenzyme A (CoA) biosynthesis is regulated by the pantothenate kinases (PanK), of which there are four active isoforms. The PanK1 isoform is selectively expressed in liver and accounted for 40% of the total PanK activity in this organ. CoA synthesis was limited using a Pank1(-/-) knockout mouse mode...
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Published in | PloS one Vol. 5; no. 6; p. e11107 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
United States
Public Library of Science
14.06.2010
Public Library of Science (PLoS) |
Subjects | |
Online Access | Get full text |
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Summary: | Coenzyme A (CoA) biosynthesis is regulated by the pantothenate kinases (PanK), of which there are four active isoforms. The PanK1 isoform is selectively expressed in liver and accounted for 40% of the total PanK activity in this organ. CoA synthesis was limited using a Pank1(-/-) knockout mouse model to determine whether the regulation of CoA levels was critical to liver function. The elimination of PanK1 reduced hepatic CoA levels, and fasting triggered a substantial increase in total hepatic CoA in both Pank1(-/-) and wild-type mice. The increase in hepatic CoA during fasting was blunted in the Pank1(-/-) mouse, and resulted in reduced fatty acid oxidation as evidenced by abnormally high accumulation of long-chain acyl-CoAs, acyl-carnitines, and triglycerides in the form of lipid droplets. The Pank1(-/-) mice became hypoglycemic during a fast due to impaired gluconeogenesis, although ketogenesis was normal. These data illustrate the importance of PanK1 and elevated liver CoA levels during fasting to support the metabolic transition from glucose utilization and fatty acid synthesis to gluconeogenesis and fatty acid oxidation. The findings also suggest that PanK1 may be a suitable target for therapeutic intervention in metabolic disorders that feature hyperglycemia and hypertriglyceridemia. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: RL CR SJ. Performed the experiments: RL JER. Analyzed the data: RL JER CR SJ. Wrote the paper: RL JER CR SJ. |
ISSN: | 1932-6203 1932-6203 |
DOI: | 10.1371/journal.pone.0011107 |