Published online before print June 7, 2001, doi: 10.1161/hh1201.092998
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© 2001 American Heart Association, Inc.
Cellular Biology |
Acute Regulation of Fatty Acid Oxidation and AMP-Activated Protein Kinase in Human Umbilical Vein Endothelial Cells
From the Departments of Medicine and Physiology (Z.D., N.R.), Boston University School of Medicine, Boston, Mass, and Diabetes and Metabolism Unit (Z.D., N.R., K.T., Y.I.), Section of Endocrinology, Boston University Medical Center, Boston, Mass.
Correspondence to Neil Ruderman, Diabetes and Metabolism Unit, Boston University Medical Center, 650 Albany St No. 820, Boston, MA 02118. E-mail nruderman{at}med-med1.bu.edu
Abstract
Abstract—It is generally accepted that endothelial cells generate most of their ATP by anaerobic glycolysis and that very little ATP is derived from the oxidation of fatty acids or glucose. Previously, we have reported that, in cultured human umbilical vein endothelial cells (HUVECs), activation of AMP-activated protein kinase (AMPK) by the cell-permeable activator 5-aminoimidazole-4-carboximide riboside (AICAR) is associated with an increase in the oxidation of 3H-palmitate. In the present study, experiments carried out with cultured HUVECs revealed the following: (1) AICAR-induced increases in palmitate oxidation during a 2-hour incubation are associated with a decrease in the concentration of malonyl coenzyme A (CoA) (an inhibitor of carnitine palmitoyl transferase 1), which temporally parallels the increase in AMPK activity and a decrease in the activity of acetyl CoA carboxylase (ACC). (2) AICAR does not stimulate either palmitate oxidation when carnitine is omitted from the medium or oxidation of the medium-chain fatty acid octanoate. (3) When intracellular lipid pools are prelabeled with 3H-palmitate, the measured rate of palmitate oxidation is 3-fold higher, and in the presence of AICAR, it accounts for nearly 40% of calculated ATP generation. (4) Incubation of HUVECs in a glucose-free medium for 2 hours causes the same changes in AMPK, ACC, malonyl CoA, and palmitate oxidation as does AICAR. (5) Under all conditions studied, the contribution of glucose oxidation to ATP production is minimal. The results indicate that the AMPK–ACC–malonyl CoA–carnitine palmitoyl transferase 1 mechanism plays a key role in the physiological regulation of fatty acid oxidation in HUVECs. They also indicate that HUVECs oxidize fatty acids from both intracellular and extracellular sources, and that when this is taken into account, fatty acids can be a major substrate for ATP generation. Finally, they suggest that AMPK is likely to be a major factor in modulating the response of the endothelium to stresses that alter its energy state.
Key Words: glucose transport • AICAR • malonyl CoA • acetyl CoA carboxylase • fuel metabolism
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