Abstract
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.
Highlights
Coenzyme A (CoA) is an essential cofactor involved in energy metabolism that carries carboxylic acid substrates and supports a multitude of oxidative and synthetic metabolic reactions, including those involved in the citric acid cycle, sterol, bile acid and fatty acid biosynthesis, and fatty acid oxidation
Our results demonstrate that PanK1 expression is necessary to maintain a normal intracellular level of CoA and to fully support the metabolic changes during the transition from the fed to the fasted state
The CoA-deficient livers have attenuated rates of fatty acid oxidation that are associated with abnormally high accumulation of long-chain acyl-CoAs and acyl-carnitines, and the development of microvesicular steatosis
Summary
Coenzyme A (CoA) is an essential cofactor involved in energy metabolism that carries carboxylic acid substrates and supports a multitude of oxidative and synthetic metabolic reactions, including those involved in the citric acid cycle, sterol, bile acid and fatty acid biosynthesis, and fatty acid oxidation (for review, see [1]). CoA is derived from vitamin B5 (pantothenate), cysteine and ATP. Pantothenate kinase (PanK) catalyzes the first committed step and controls the overall rate of CoA biosynthesis [1,2,3]. There are three genes that express four characterized isoforms of PanK. PanK1a and PanK1b are encoded by the same gene and arise from the use of alternate initiation exons [4], whereas the PanK2 and PanK3 isoforms are encoded by distinct genes [5,6]. The PanK isoforms are feedback regulated by CoA thioesters [4,5,7], and the loss or alteration of feedback regulation by mutations in PanK result in dysregulated CoA production [5,8]. PanK expression levels contribute to determination of the cellular CoA content [9,10]
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