Potential mechanisms and consequences of cardiac triacylglycerol accumulation in insulin-resistant rats
1 Cardiovascular Research Group and Departments of 2 Pediatrics and 3 Surgery, Faculty of Medicine, The University of Alberta, Edmonton, Alberta, Canada T6G 2S2 The accumulation of intracellular triacylglycerol (TG) is highly correlated with muscle insulin resistance. However, it is controversial...
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Published in | American journal of physiology: endocrinology and metabolism Vol. 284; no. 5; pp. E923 - E930 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.05.2003
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Subjects | |
Online Access | Get full text |
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Summary: | 1 Cardiovascular Research Group and Departments of
2 Pediatrics and 3 Surgery, Faculty
of Medicine, The University of Alberta, Edmonton, Alberta,
Canada T6G 2S2
The accumulation of
intracellular triacylglycerol (TG) is highly correlated with muscle
insulin resistance. However, it is controversial whether the
accumulation of TG is the result of increased fatty acid supply,
decreased fatty acid oxidation, or both. Because abnormal fatty acid
metabolism is a key contributor to the pathogenesis of diabetes-related
cardiovascular dysfunction, we examined fatty acid and glucose
metabolism in hearts of insulin-resistant JCR:LA-cp rats. Isolated
working hearts from insulin-resistant rats had glycolytic rates that
were reduced to 50% of lean control levels ( P < 0.05). Cardiac TG content was increased by 50% ( P < 0.05) in the insulin-resistant rats, but palmitate oxidation rates
remained similar between the insulin-resistant and lean control rats.
However, plasma fatty acids and TG levels, as well as cardiac fatty
acid-binding protein (FABP) expression, were significantly increased in
the insulin-resistant rats. AMP-activated protein kinase (AMPK) plays a
major role in the regulation of cardiac fatty acid and glucose
metabolism. When activated, AMPK increases fatty acid oxidation by
inhibiting acetyl-CoA carboxylase (ACC) and reducing malonyl-CoA
levels, and it decreases TG content by inhibiting glycerol-3-phosphate
acyltransferase (GPAT), the rate-limiting step in TG synthesis. The
activation of AMPK also stimulates cardiac glucose uptake and
glycolysis. We thus investigated whether a decrease in AMPK activity
was responsible for the reduced cardiac glycolysis and increased TG
content in the insulin-resistant rats. However, we found no significant
difference in AMPK activity. We also found no significant difference in
various established downstream targets of AMPK: ACC activity,
malonyl-CoA levels, carnitine palmitoyltransferase I activity, or GPAT
activity. We conclude that hearts from insulin-resistant JCR:LA-cp rats
accumulate substantial TG as a result of increased fatty acid supply
rather than from reduced fatty acid oxidation. Furthermore, the
accumulation of cardiac TG is associated with a reduction in
insulin-stimulated glucose metabolism.
AMP-activated protein kinase; glycolysis; acetyl-CoA carboxylase; glycerol-3-phosphate acyltransferase |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0193-1849 1522-1555 |
DOI: | 10.1152/ajpendo.00360.2002 |