AMPK control of myocardial fatty acid metabolism fluctuates with the intensity of insulin-deficient diabetes.
Flexibility in substrate selection is essential for the heart to maintain production of energy and contractile function, and is managed through multiple mechanisms including PPAR-alpha and AMP-activated protein kinase (AMPK). Rats injected with 55 mg/kg STZ (D55) were kept for 4 days (acute diabetes; D55-A) prior to termination. Fatty acid (FA) oxidation increased in D55-A hearts, with no significant change in gene expression of PPAR-alpha, or its downstream targets. However, both AMPK and ACC phosphorylation were significantly higher in these hearts, effects that were reversed by insulin. Unexpectedly, when the duration of diabetes in D55 rats was extended to 6 weeks (chronic diabetes; D55-C), AMPK and ACC phosphorylation were comparable in control and D55-C hearts. In D55-C rat hearts, lack of AMPK activation was closely associated to an overload of plasma and cardiac lipids. To validate the relationship between lipids and cardiac AMPK activation, we either induced more severe diabetes (100 mg/kg STZ to provoke both hyperglycemia and hyperlipidemia acutely; D100-A) or infused intralipid (IL) to enlarge circulating lipids. There was no difference in cardiac AMPK and ACC phosphorylation in D100-A rats compared to control. Measurement of AMPK and ACC phosphorylation in control and D55-A hearts revealed that their phosphorylation was inhibited by acute intralipid infusion. Our data suggest that activation of AMPK is an adaptation that would ensure adequate cardiac energy production when glucose utilization is compromised. However, in severe diabetes, with the addition of augmented plasma and heart lipids, AMPK activation is prevented, and control of FA oxidation is likely through alternate mechanisms. Given that AMPK plays an important role in preventing cardiac ischemic/reperfusion damage, it is possible that in these diabetic hearts, the accelerated damage observed during exposure to ischemia/reperfusion could be a likely outcome of a compromised activation of AMPK.
Kewalramani
Girish
G
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, BC, Canada.
An
Ding
D
Kim
Min Suk
MS
Ghosh
Sanjoy
S
Qi
Dake
D
Abrahani
Ashraf
A
Pulinilkunnil
Thomas
T
Sharma
Vijay
V
Wambolt
Richard B
RB
Allard
Michael F
MF
Innis
Sheila M
SM
Rodrigues
Brian
B
D055372:AMP-Activated Protein Kinases; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism*; D006943:Hyperglycemia / Q000139:chemically induced / Q000201:enzymology; D006949:Hyperlipidemias / Q000139:chemically induced / Q000201:enzymology; D007328:Insulin / Q000172:deficiency*; D008297:Male; D009097:Multienzyme Complexes; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D017208:Rats, Wistar
D005227:Fatty Acids; D007328:Insulin; D009097:Multienzyme Complexes; D047493:PPAR alpha; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases