Oxfenicine, a partial fatty acid oxidation inhibitor results in lower myocardial FFA uptakes and lactate production during demand-induced ischemia

1. Cultured calvaria cells oxidized palmitate and octanoate to CO2 and water-soluble products. 2. When these cells were treated for 6 days with 0.025 and 0.25 mM-dichloromethanediphosphonate, oxidation of palmitate was increased, whereas that of octanoate was influenced less. 3. When the rate of oxidation was raised by increasing the palmitate concentration in the medium, the effect of the diphosphonate was decreased and finally disappeared. 4. 1-Hydroxyethane-1,1-diphosphonate had only minor effects. 5. The increase in palmitate oxidation appeared 2 days after the addition of dichloromethanediphosphonate, simultaneously with a fall in lactate production. (Inhibition of glycolysis by diphosphonates has already been shown.) 6. Cycloheximide, an inhibitor of protein synthesis, did not influence the effect of dichloromethanediphosphonate on the oxidation of palmitate and the production of lactate. 7. Cells cultured with dichloromethanediphosphonate showed a faster uptake of palmitic acid than did control cells. However, this observation did not explain the increased palmitate oxidation, since uptake was much faster than oxidation, and was therefore not the rate-limiting step. 8. 2-Bromopalmitate, an inhibitor of fatty acid oxidation, did not influence the inhibition of glycolysis by the diphosphonates. This inhibition, therefore, did not result from the increased oxidation of palmitate. It is also unlikely that the increased oxidation of palmitate is connected with the inhibition of glycolysis.

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Acetyl-CoA from inflammation-induced fatty acids oxidation promotes hepatic malate-aspartate shuttle activity and glycolysis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00061.2018 ◽

2018 ◽

Vol 315 (4) ◽

pp. E496-E510 ◽

Cited By ~ 12

Author(s):

Tongxin Wang ◽

Weilei Yao ◽

Ji Li ◽

Qiongyu He ◽

Yafei Shao ◽

...

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Lactate Production ◽

Acid Oxidation ◽

Oxidative Decarboxylation ◽

Nutrient Metabolism ◽

Acetyl Coa ◽

Inflammatory Stress ◽

Malate Aspartate Shuttle

Hepatic metabolic syndrome is associated with inflammation, as inflammation stimulates the reprogramming of nutrient metabolism and hepatic mitochondria-generated acetyl-CoA, but how acetyl-CoA affects the reprogramming of nutrient metabolism, especially glucose and fatty acids, in the condition of inflammation is still unclear. Here, we used an acute inflammation model in which pigs were injected with lipopolysaccharide (LPS) and found that hepatic glycolysis and fatty acid oxidation are both promoted. Acetyl-proteome profiling of LPS-infected pigs liver showed that inflammatory stress exacerbates the acetylation of mitochondrial proteins. Both mitochondrial glutamate oxaloacetate transaminase 2 (GOT2) and malate dehydrogenase 2 (MDH2) were acetylated, and the malate-aspartate shuttle (MAS) activity was stimulated to maintain glycolysis. With the use of 13C-carbon tracing in vitro, acetyl-CoA was found to be mainly supplied by lipid-derived fatty acid oxidation rather than glucose-derived pyruvate oxidative decarboxylation, while glucose was mainly used for lactate production in response to inflammatory stress. The results of the mitochondrial experiment showed that acetyl-CoA directly increases MDH2 and, in turn, the GOT2 acetylation level affects MAS activity. Treatment with palmitate in primary hepatocytes from LPS-injected pigs increased the hepatic production of acetyl-CoA, pyruvate, and lactate; MAS activity; and hepatic MDH2 and GOT2 hyperacetylation, while the deficiency of long-chain acetyl-CoA dehydrogenase resulted in the stabilization of these parameters. These observations suggest that acetyl-CoA produced by fatty acid oxidation promotes MAS activity and glycolysis via nonenzymatic acetylation during the inflammatory stress response.

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Effect of the fatty acid oxidation inhibitor 2-tetradecylglycidic acid (TDGA) on glucose and fatty acid oxidation in isolated rat soleus muscle

International Journal of Biochemistry ◽

10.1016/0020-711x(88)90479-x ◽

1988 ◽

Vol 20 (2) ◽

pp. 155-160 ◽

Cited By ~ 8

Author(s):

Robert W. Tuman ◽

John M. Joseph ◽

Henry J. Brentzel ◽

Gene F. Tutwiler

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Soleus Muscle ◽

Acid Oxidation ◽

Oxidation Inhibitor ◽

Rat Soleus Muscle ◽

Isolated Rat

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Increased nonoxidative glycolysis despite continued fatty acid uptake during demand-induced myocardial ischemia

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00976.2001 ◽

2002 ◽

Vol 282 (5) ◽

pp. H1871-H1878 ◽

Cited By ~ 27

Author(s):

Margaret P. Chandler ◽

Hazel Huang ◽

Tracy A. McElfresh ◽

William C. Stanley

Keyword(s):

Fatty Acid ◽

Coronary Artery ◽

Fatty Acid Oxidation ◽

Lactate Production ◽

Fatty Acid Uptake ◽

Anterior Wall ◽

Acid Oxidation ◽

Acid Uptake ◽

Substrate Uptake ◽

Exogenous Fatty Acid

During stress, patients with coronary artery disease frequently fail to increase coronary flow and myocardial oxygen consumption (MV˙o 2) in response to a greater demand for oxygen, resulting in “demand-induced” ischemia. We tested the hypothesis that dobutamine infusion with flow restriction stimulates nonoxidative glycolysis without a change in MV˙o 2 or fatty acid uptake. Measurements were made in the anterior wall of anesthetized open-chest swine hearts ( n = 7). The left anterior descending (LAD) coronary artery flow was controlled via an extracorporeal perfusion circuit, and substrate uptake and oxidation were measured with radiotracers. Demand-induced ischemia was produced with intravenous dobutamine (15 μg · kg−1 · min−1) and 20% reduction in LAD flow for 20 min. Despite no change in MV˙o 2, there was a switch from lactate uptake (5.9 ± 3.1) to production (74.5 ± 16.3 μmol/min), glycogen depletion (66%), and increased glucose uptake (105%), but no change in anterior wall power or the index of anterior wall energy efficiency. There was no change in the rate of tracer-measured fatty acid uptake; however, exogenous fatty acid oxidation decreased by 71%. Thus demand-induced ischemia stimulated nonoxidative glycolysis and lactate production, but did not effect fatty acid uptake despite a fall in exogenous fatty acid oxidation.

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