Amp-activated Protein Kinase and the Coordination of Hepatic Fatty Acid Metabolism of Starved/carbohydrate-refed Rats

Acute increases in the concentration of malonyl CoA play a pivotal role in mediating the decrease in fatty acid oxidation that occurs in many tissues during refeeding after a fast. In this study, we assess whether such increases in malonyl CoA in liver could be mediated by malonyl CoA decarboxylase (MCD), as well as acetyl CoA carboxylase (ACC). In addition, we examine how changes in the activity of ACC, MCD and other enzymes that govern fatty acidand glycerolipid synthesis relate temporally to alterations in the activities of the fuel sensing enzyme AMP-activated protein kinase (AMPK). Rats starved for 48h and refed a carbohydrate chow diet for 1, 3, 12 and 24h were studied. Refeeding caused a 40% decrease in the activity of the α1isoform of AMPK within 1h, with additional decreases in α1 AMPK activity and a decrease in α2 AMPK occurring between 1-24 h. At 1 hr, the decrease in AMPK activity was associated with an 8-fold increase in the activity of the α1 isoform of ACC and a 30% decrease in the activity of MCD, two enzymes thought to be regulated by AMPK. Also, the concentration of malonyl CoA was increased by 50%. Between 1h and 3h of refeeding, additional increases in the activity of ACC and decreases in MCD were observed, as was a further 2-fold increase in malonyl CoA. Increases in the activity (60%) and abundance (12-fold) of fatty acid synthase (FAS) occurred predominantly between 3-24h and increases in the activity of mitochondrial glycerol phosphate acyltransferase (GPAT) and acyl CoA: diaclyglycerol acyltransferase (DGAT) at 12 and 24 h. The results strongly suggest that early changes in the activity of MCD, as well as ACC, contribute to the increase in hepatic malonyl CoA in the starved-refed rat. They also suggest that the changes in these enzymes, and later occurring increases in enzymes regulating fatty acid and glycerolipid synthesis, could be coordinated by AMPK. AMPK and the starved/fed transition in liver 3