Abstract
Changes in the concentration of malonyl-CoA in many tissues have been related to alterations in the activity of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in its formation. In contrast, little is known about the physiological role of malonyl-CoA decarboxylase (MCD), an enzyme responsible for malonyl-CoA catabolism. In this study, we examined the effects of voluntary exercise on MCD activity in rat liver, skeletal muscle, and adipose tissue. In addition, the activity of sn-glycerol-3-phosphate acyltransferase (GPAT), which like MCD and ACC can be regulated by AMP-activated protein kinase (AMPK), was assayed. Thirty min after the completion of a treadmill run, MCD activity was increased approximately 2-fold, malonyl-CoA levels were reduced, and ACC and GPAT activities were diminished by 50% in muscle and liver. These events appeared to be mediated via activation of AMPK since: 1) AMPK activity was concurrently increased by exercise in both tissues; 2) similar findings were observed after the injection of 5-amino 4 imidazole carboxamide, an AMPK activator; 3) changes in the activity of GPAT and ACC paralleled that of MCD; and 4) the increase in MCD activity in muscle was reversed in vitro by incubating immunoprecipitated enzyme from the exercised muscle with protein phosphatase 2A, and it was reproduced by incubating immunopurified MCD from resting muscle with purified AMPK. An unexpected finding was that exercise caused similar changes in the activities of ACC, MCD, GPAT, and AMPK and the concentration of malonyl-CoA in adipose tissue. MCD, GPAT, and ACC are coordinately regulated by AMPK in liver and adipose tissue in response to exercise, and except for GPAT, also in muscle. The results suggest that AMPK activation plays a major role in regulating lipid metabolism in many cells following exercise. They also suggest that in each of them, it acts to increase fatty acid oxidation and decrease its esterification.
Highlights
Changes in the concentration of malonyl-CoA in many tissues have been related to alterations in the activity of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in its formation
A similar pattern of events was observed in liver, in which exercise increased malonylCoA decarboxylase (MCD) activity 2-fold and caused the concentration of malonyl-CoA and ACC activity to decrease by 50% (Fig. 1), and in epididymal adipose tissue, in which exercise increased MCD activity by 70% and decreased the concentration of malonyl-CoA and the activity of ACC by 40 – 60% (Fig. 1)
2) In all three tissues, the activities of MCD and ACC are coordinately regulated by AMPK. 3) glycerophosphate acyltransferase (GPAT) activity is diminished in liver and adipose tissue after exercise, and this too appears to be regulated by AMPK. 4) The net effect of these changes should be to increase the oxidation of fatty acids and to diminish their esterification
Summary
Changes in the concentration of malonyl-CoA in many tissues have been related to alterations in the activity of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in its formation. A multitude of studies in such tissues as liver and muscle have clearly shown that increases and decreases in malonyl-CoA levels correlate closely with changes in ACC activity [2,3,4] It is less clear whether malonylCoA decarboxylase (MCD), an enzyme that degrades malonylCoA, regulates its concentration under physiological conditions. The present study explores the effect of voluntary exercise on MCD activity in rat liver, skeletal muscle, and adipose tissue and how observed changes relate temporally to alterations in the activities of ACC, AMPK, and glycerophosphate acyltransferase (GPAT), another enzyme shown previously to be regulated by AMPK [16] and malonyl-CoA concentration. Since it has recently been suggested that measurements of MCD activity may vary with the assay used [7], in some studies, results obtained with spectrophotometric and radiometric methods were compared
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