Inhibition of fatty acid and cholesterol synthesis by stimulation of AMP-activated protein kinase.

摘要: AMP-activated protein kinase is a multisubstrate that, in liver, inactivates both acetyl-CoA carboxylase, the rate-limiting enzyme of fatty acid synthesis, and 3-hydroxy-3-methyl-glutaryl-CoA reductase, cholesterol synthesis. AICAR (5-amino 4-imidazolecarboxamide ribotide, ZMP) was found to stimulate up 10-fold rat liver kinase, with half-maximal effect at approximately 5 mM. In accordance previous observations, addition suspensions isolated hepatocytes 50-500 microM AICAriboside, nucleoside corresponding ZMP, resulted accumulation millimolar concentrations latter. This accompanied by dose-dependent inactivation carboxylase 3-hydroxy-3-methylglutaryl-CoA reductase. Addition AICAriboside hepatocyte incubated presence various substrates, including glucose lactate/pyruvate, caused parallel inhibition With lactate/pyruvate (10/1 mM), obtained 100 microM, near-complete 500 AICAriboside. These findings open new perspectives for simultaneous control triglyceride synthesis pharmacological stimulators kinase.