Pantothenate kinase 1 is required to support the metabolic transition from the fed to the fasted state.
Pantothenate kinase 1 is required to support the metabolic transition from the fed to the fasted state.
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DOI：
10.1371/journal.pone.0011107
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发表时间：
2010-06-14
期刊：
影响因子：
3.7
通讯作者：
Jackowski S
中科院分区：
文献类型：
--
作者：
Leonardi R;Rehg JE;Rock CO;Jackowski S
辅酶A （CoA）的生物合成受泛酸激酶（PanK）的调控，其中有四种活性亚型。PanK1亚型在肝脏中选择性表达，占该器官PanK总活性的40%。使用Pank1−/−敲除小鼠模型来限制CoA的合成，以确定CoA水平的调节是否对肝功能至关重要。PanK1的消除降低了肝脏CoA水平，在PanK1−/−和野生型小鼠中，禁食引发了肝脏总CoA的大幅增加。在Pank1−/−小鼠中，禁食期间肝脏辅酶a的增加被减弱，并导致脂肪酸氧化减少，这可以通过长链酰基辅酶a、酰基肉碱和甘油三酯以脂滴形式异常高的积累来证明。Pank1−/−小鼠在禁食期间由于糖异生受损而出现低血糖，尽管生酮正常。这些数据说明了禁食期间PanK1和肝脏CoA水平升高对支持从葡萄糖利用和脂肪酸合成到糖异生和脂肪酸氧化的代谢转变的重要性。研究结果还表明，PanK1可能是以高血糖和高甘油三酯血症为特征的代谢紊乱的治疗干预的合适靶点。
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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影响因子：
4.8
作者：
Fan, CY;Pan, J;Reddy, JK
通讯作者：
Reddy, JK
影响因子：
4.8
作者：
Fiermonte, Giuseppe;Paradies, Eleonora;Palmieri, Ferdinando
通讯作者：
Palmieri, Ferdinando
影响因子：
3.5
作者：
Kelly, CL;Rhead, WJ;Wood, PA
通讯作者：
Wood, PA
影响因子：
3.6
作者：
BLUNT, AD;CHEESMAN, EM;COPPING, AM
通讯作者：
COPPING, AM
DOI：
10.1042/bj20080709
发表时间：
2008-08-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Jitrapakdee S;St Maurice M;Rayment I;Cleland WW;Wallace JC;Attwood PV
通讯作者：
Attwood PV