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J Biol Chem, Vol. 273, Issue 37, 23758-23763, September 11, 1998
From the Department of Cell Biology, Institute for Cancer Research,
The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway
To examine the role of AMP-activated protein
kinase (AMPK; EC 2.7.1.109) in the regulation of autophagy, rat
hepatocytes were incubated with the AMPK proactivators, adenosine,
5-amino-4-imidazole carboxamide riboside (AICAR), or
N6-mercaptopurine riboside.
Autophagic activity was inhibited by all three nucleosides, AICAR and
N6-mercaptopurine riboside being more
potent (IC50 = 0.3 mM) than adenosine
(IC50 = 1 mM). 2'-Deoxycoformycin, an adenosine
deaminase (EC 3.5.4.4) inhibitor, increased the potency of adenosine
5-fold, suggesting that the effectiveness of adenosine as an autophagy inhibitor was curtailed by its intracellular deamination.
5-Iodotubercidin, an adenosine kinase (EC 2.7.1.20) inhibitor,
abolished the effects of all three nucleosides, indicating that
they needed to be phosphorylated to inhibit autophagy. A
5-iodotubercidin-suppressible phosphorylation of AICAR to
5-aminoimidazole-4-carboxamide riboside monophosphate was confirmed by
chromatographic analysis. AICAR, up to 0.4 mM, had no
significant effect on intracellular ATP concentrations. Because
activated AMPK phosphorylates and inactivates
3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.88), the
rate-limiting enzyme in cholesterol synthesis, the strong inhibition of
hepatocytic cholesterol synthesis by all three nucleosides confirmed
their ability to activate AMPK under the conditions used. Lovastatin and simvastatin, inhibitors of HMG-CoA reductase, strongly
suppressed cholesterol synthesis while having no effect on autophagic
activity, suggesting that AMPK inhibits autophagy independently
of its effects on HMG-CoA reductase and cholesterol
metabolism.
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