5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) Effect on Glucose Production, but Not Energy Metabolism, Is Independent of Hepatic AMPK in Vivo
5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) Effect on Glucose Production, but Not Energy Metabolism, Is Independent of Hepatic AMPK in Vivo
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DOI：
10.1074/jbc.m113.528232
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发表时间：
2014-02-28
影响因子：
4.8
通讯作者：
Wasserman, David H.
中科院分区：
文献类型：
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作者：
Hasenour, Clinton M.;Ridley, D. Emerson;Wasserman, David H.
代谢应激，以及一些抗糖尿病药物，增加肝核苷酸单磷酸（NMP）水平，激活amp活化的蛋白激酶（AMPK），并抑制葡萄糖的产生。我们测试了肝脏AMPK对体内NMP急性升高对代谢的影响的必要性。5-氨基咪唑-4-羧酰胺1- β -d-核氟烷苷(AICAR； 8 mg中心点kg(-1)min(-1))-血糖钳在固定葡萄糖存在下引起野生型（α 1 α 2(lox/lox)）和肝脏特异性AMPK敲除小鼠（α 1 α 2(lox/lox) + Albcre） NMP的增加。空腹5 h α 1 α 2（lox/lox）和α 1 α 2(lox/lox) + Albcre小鼠的葡萄糖动力学相同。AMPK不需要aicar介导的葡萄糖产生抑制和葡萄糖消失增加。这些结果表明AMPK对于正常的5小时空腹葡萄糖动力学和aicar介导的葡萄糖产生抑制是不必要的。此外，在AICAR给药期间，血浆脂肪酸和甘油三酯也独立于肝脏AMPK下降。虽然AICAR的血糖调节作用被证明是独立于AMPK的，但这些研究为AMPK能量传感器范式提供了体内支持。在α 1 α 2（lox/lox）组中，AICAR使肝脏能量电荷降低了约20%，在α 1 α 2(lox/lox) + Albcre组中，这种情况加重了约2倍。这相当于α 1 α 2(lox/lox) + Albcre中AMP/ATP升高约6倍。与腺嘌呤核苷酸的影响一致，α 1 α 2(lox/lox) + Albcre肝脏的最大线粒体呼吸比α 1 α 2（lox/lox）肝脏低约30%。线粒体氧化磷酸化效率降低25%。综上所述，这些结果表明NMP在体内抑制葡萄糖生成的能力与肝脏AMPK无关。相反，AMPK促进线粒体功能，并在AICAR给药期间防止ATP的急剧下降。
Metabolic stress, as well as several antidiabetic agents, increases hepatic nucleotide monophosphate (NMP) levels, activates AMP-activated protein kinase (AMPK), and suppresses glucose production. We tested the necessity of hepatic AMPK for the in vivo effects of an acute elevation in NMP on metabolism. 5-Aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside (AICAR; 8 mg center dot kg(-1)min(-1))-euglycemic clamps were performed to elicit an increase in NMP in wild type (alpha 1 alpha 2(lox/lox)) and liver-specific AMPK knock-out mice (alpha 1 alpha 2(lox/lox) + Albcre) in the presence of fixed glucose. Glucose kinetics were equivalent in 5-h fasted alpha 1 alpha 2(lox/lox) and alpha 1 alpha 2(lox/lox) + Albcre mice. AMPK was not required for AICAR-mediated suppression of glucose production and increased glucose disappearance. These results demonstrate that AMPK is unnecessary for normal 5-h fasting glucose kinetics and AICAR-mediated inhibition of glucose production. Moreover, plasma fatty acids and triglycerides also decreased independently of hepatic AMPK during AICAR administration. Although the glucoregulatory effects of AICAR were shown to be independent of AMPK, these studies provide in vivo support for the AMPK energy sensor paradigm. AICAR reduced hepatic energy charge by approximate to 20% in alpha 1 alpha 2(lox/lox), which was exacerbated by approximate to 2-fold in alpha 1 alpha 2(lox/lox) + Albcre. This corresponded to a approximate to 6-fold rise in AMP/ATP in alpha 1 alpha 2(lox/lox) + Albcre. Consistent with the effects on adenine nucleotides, maximal mitochondrial respiration was approximate to 30% lower in alpha 1 alpha 2(lox/lox) + Albcre than alpha 1 alpha 2(lox/lox) livers. Mitochondrial oxidative phosphorylation efficiency was reduced by 25%. In summary, these results demonstrate that the NMP capacity to inhibit glucose production in vivo is independent of liver AMPK. In contrast, AMPK promotes mitochondrial function and protects against a more precipitous fall in ATP during AICAR administration.