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Hasenour 2014 J Biol Chem

From Bioblast
Publications in the MiPMap
Hasenour CM, Ridley DE, Hughey CC, James FD, Donahue EP, Shearer J, Viollet B, Foretz M, Wasserman DH (2014) 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) effect on glucose production, but not energy metabolism, is independent of hepatic AMPK in vivo. J Biol Chem 289:5950-9.

» PMID:24403081

Hasenour CM, Ridley DE, Hughey CC, James FD, Donahue EP, Shearer J, Viollet B, Foretz M, Wasserman DH (2014) J Biol Chem

Abstract: Metabolic stress, as well as several antidiabetic agents, increase hepatic nucleotide monophosphate levels (NMP), activate AMP-activated protein kinase (AMPK), and suppress glucose production. We tested the necessity of hepatic AMPK for the in vivo effects of an acute elevation in NMP on metabolism. AICAR (8mg·kg-1·min-1)-euglycemic clamps were performed to elicit an increase in NMP in wild-type (α1α2lox/lox) and liver-specific AMPK-knockout mice (α1α2lox/lox+Albcre) in the presence of fixed glucose. Glucose kinetics were equivalent in 5hr fasted (Basal) α1α2lox/lox and α1α2lox/lox+Albcre mice. AMPK was not required for AICAR-mediated suppression of glucose production and increased glucose clearance. These results demonstrate that AMPK is unnecessary for normal basal 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 (EC) by ~20% in α1α2lox/lox which was exacerbated by ~2-fold in α1α2lox/lox+Albcre. This corresponded to a ~6-fold rise in AMP/ATP in α1α2lox/lox+Albcre. Consistent with the effects on adenine nucleotides, maximal mitochondrial respiration was ~30% lower in α1α2lox/lox+Albcre than α1α2lox/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. Keywords: AICAR, AMP, AMP kinase, AMP-activated kinase (AMPK), Energy metabolism, Fat metabolism, Liver metabolism, in vivo

O2k-Network Lab: US TN Nashville Wasserman DH, CA Calgary Shearer J


Labels: MiParea: Respiration, Genetic knockout;overexpression 


Organism: Mouse  Tissue;cell: Liver  Preparation: Isolated mitochondria 

Regulation: ATP  Coupling state: LEAK, OXPHOS, ET  Pathway: N, ROX  HRR: Oxygraph-2k