Fatty acid oxidation and the regulation of malonyl-CoA in human muscle
Fatty acid oxidation and the regulation of malonyl-CoA in human muscle. P N Båvenholm , J Pigon , A K Saha , N B Ruderman and S Efendic Department of Emergency and Cardiovascular Medicine, Karolinska Hospital and Institute, Stockholm, Sweden. Abstract Questions concerning whether malonyl-CoA is regu...
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Published in | Diabetes (New York, N.Y.) Vol. 49; no. 7; pp. 1078 - 1083 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Alexandria, VA
American Diabetes Association
01.07.2000
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Subjects | |
Online Access | Get full text |
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Summary: | Fatty acid oxidation and the regulation of malonyl-CoA in human muscle.
P N Båvenholm ,
J Pigon ,
A K Saha ,
N B Ruderman and
S Efendic
Department of Emergency and Cardiovascular Medicine, Karolinska Hospital and Institute, Stockholm, Sweden.
Abstract
Questions concerning whether malonyl-CoA is regulated in human muscle and whether malonyl-CoA modulates fatty acid oxidation
are still unanswered. To address these questions, whole-body fatty acid oxidation and the concentration of malonyl-CoA, citrate,
and malate were determined in the vastus lateralis muscle of 16 healthy nonobese Swedish men during a sequential euglycemic-hyperinsulinemic
clamp. Insulin was infused at rates of 0.25 and 1.0 mU x kg(-1) x min(-1), and glucose was infused at rates of 2.0 +/- 0.2
and 8.1 +/- 0.7 mg x kg(-1) x min(-1), respectively. During the low-dose insulin infusion, whole-body fatty acid oxidation,
as determined by indirect calorimetry, decreased by 22% from a basal rate of 0.94 +/- 0.06 to 0.74 +/- 0.07 mg x kg(-1) x
min(-1) (P = 0.005), but no increase in malonyl-CoA was observed. In contrast, during the high-dose insulin infusion, malonyl-CoA
increased from 0.20 +/- 0.01 to 0.24 +/- 0.01 nmol/g (P < 0.001), and whole-body fatty acid oxidation decreased by an additional
41% to 0.44 +/- 0.06 mg x kg(-1) x min(-1) (P < 0.001). The increase in malonyl-CoA was associated with 30-50% increases in
the concentrations of citrate (102 +/- 6 vs. 137 +/- 7 nmol/g, P < 0.001), an allosteric activator of the rate-limiting enzyme
in the malonyl-CoA formation, acetyl-CoA carboxylase, and malate (80 +/- 6 vs. 126 +/- 9 nmol/g, P = 0.002), an antiporter
for citrate efflux from the mitochondria. Significant correlations were observed between the concentration of malonyl-CoA
and both glucose utilization (r = 0.53, P = 0.002) and the sum of the concentrations of citrate and malate (r = 0.52, P <
0.001), a proposed index of the cytosolic concentration of citrate. In addition, an inverse correlation between malonyl-CoA
concentration and fatty acid oxidation was observed (r = -0.32, P = 0.03). The results indicate that an infusion of insulin
and glucose at a high rate leads to increases in the concentration of malonyl-CoA in skeletal muscle and to decreases in whole-body
and, presumably, muscle fatty acid oxidation. Furthermore, they suggest that the increase in malonyl-CoA in this situation
is due, at least in part, to an increase in the cytosolic concentration of citrate. Because cytosolic citrate is also an inhibitor
of phosphofructokinase, an attractive hypothesis is that changes in its concentration are part of an autoregulatory mechanism
by which glucose modulates its own use and the use of fatty acids as fuels for skeletal muscle. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0012-1797 1939-327X |
DOI: | 10.2337/diabetes.49.7.1078 |