Hepatic de novo synthesis of glucose 6-phosphate is not affected in peroxisome proliferator-activated receptor α-deficient mice but is preferentially directed toward hepatic glycogen stores after a short term fast
Hepatic de novo synthesis of glucose 6-phosphate is not affected in peroxisome proliferator-activated receptor α-deficient mice but is preferentially directed toward hepatic glycogen stores after a short term fast
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DOI：
10.1074/jbc.m310067200
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发表时间：
2004-03-05
影响因子：
4.8
通讯作者：
Kuipers, F
中科院分区：
文献类型：
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作者：
Bandsma, RHJ;van Dijk, TH;Kuipers, F
除了β-氧化受损外，PPARpha缺陷(-/-)小鼠在长时间禁食期间还会出现低血糖，这表明肝脏葡萄糖代谢发生了变化。我们应用新的同位素方法，比较了短期禁食后野生型(WT)和PPARpha(-/-)小鼠体内的肝脏葡萄糖代谢。禁食9h后，给小鼠灌胃[U-C-13]葡萄糖、[2-C-13]甘油、[1-H-2]半乳糖和扑热息痛6h，定时采集血和尿。血糖浓度保持不变，两组之间没有差异。禁食15h后，WT和PPARpha(-/-)小鼠的肝糖原含量分别为69+/-11和90+/-31mumol/g肝。WT组和PPARpha(-/-)组小鼠对6-磷酸葡萄糖的糖异生通量无差异(分别为157+/-9和153+/-9mumol/kg/min)。然而，PPARα(-/-)小鼠的血糖异生流量减少(即142+/-9比124+/-13mumol/kg/min)(p<；0.05)，这是观察到PPARα(-/-)小鼠肝脏葡萄糖产生减少(-15%)的原因。编码葡萄糖-6-磷酸水解酶(G6ph)的基因在PPARα(-/-)小鼠中的表达低于WT小鼠。总而言之，PPARα(-/-)小鼠在中度禁食期间能够维持正常的葡萄糖6-磷酸葡萄糖异生流量，尽管它们无法上调β-氧化。然而，这种糖异生流量更多地指向糖原，导致肝脏葡萄糖输出减少。这与PPARα缺陷小鼠G6ph的表达下调有关。
Apart from impaired beta-oxidation, Pparalpha-deficient (Pparalpha(-/-)) mice suffer from hypoglycemia during prolonged fasting, suggesting alterations in hepatic glucose metabolism. We compared hepatic glucose metabolism in vivo in wild type (WT) and Pparalpha(-/-) mice after a short term fast, applying novel isotopic methods. After a 9-h fast, mice were infused with [U-C-13] glucose, [2-C-13] glycerol, [1-H-2]galactose, and paracetamol for 6 h, and blood and urine was collected in timed intervals. Plasma glucose concentrations remained constant and were not different between the groups. Hepatic glycogen content was 69 +/- 11 and 90 +/- 31 mumol/g liver after 15 h of fasting in WT and Pparalpha(-/-) mice, respectively. The gluconeogenic flux toward glucose 6-phosphate was not different between the groups (i.e. 157 +/- 9 and 153 +/- 9 mumol/kg/min in WT and Pparalpha(-/-) mice, respectively). The gluconeogenic flux toward plasma glucose, however, was decreased in PPARalpha(-/-) mice (i.e. 142 +/- 9 versus 124 +/- 13 mumol/kg/min) (p < 0.05), accounting for the observed decrease (-15%) in hepatic glucose production in Ppar alpha(-/-) mice. Expression of the gene encoding glucose-6-phosphate hydrolase (G6ph) was lower in the PPAR alpha(-/-) mice compared with WT mice. In conclusion, Ppar alpha(-/-) mice were able to maintain a normal total gluconeogenic flux to glucose 6-phosphate during moderate fasting, despite their inability to up-regulate beta-oxidation. However, this gluconeogenic flux was directed more toward glycogen, leading to a decreased hepatic glucose output. This was associated with a down-regulation of the expression of G6ph in PPAR alpha-deficient mice.