scholarly journals Acyl Coenzyme A Thioesterase 7 Regulates Neuronal Fatty Acid Metabolism To Prevent Neurotoxicity

2013 ◽  
Vol 33 (9) ◽  
pp. 1869-1882 ◽  
Author(s):  
Jessica M. Ellis ◽  
G. William Wong ◽  
Michael J. Wolfgang

Numerous neurological diseases are associated with dysregulated lipid metabolism; however, the basic metabolic control of fatty acid metabolism in neurons remains enigmatic. Here we have shown that neurons have abundant expression and activity of the long-chain cytoplasmic acyl coenzyme A (acyl-CoA) thioesterase 7 (ACOT7) to regulate lipid retention and metabolism. Unbiased and targeted metabolomic analysis of fasted mice with a conditional knockout of ACOT7 in the nervous system, Acot7 N−/− , revealed increased fatty acid flux into multiple long-chain acyl-CoA-dependent pathways. The alterations in brain fatty acid metabolism were concomitant with a loss of lean mass, hypermetabolism, hepatic steatosis, dyslipidemia, and behavioral hyperexcitability in Acot7 N − / − mice. These failures in adaptive energy metabolism are common in neurodegenerative diseases. In agreement, Acot7 N − / − mice exhibit neurological dysfunction and neurodegeneration. These data show that ACOT7 counterregulates fatty acid metabolism in neurons and protects against neurotoxicity.

2006 ◽  
Vol 281 (48) ◽  
pp. 37246-37255 ◽  
Author(s):  
Lei O. Li ◽  
Douglas G. Mashek ◽  
Jie An ◽  
Scott D. Doughman ◽  
Christopher B. Newgard ◽  
...  

1981 ◽  
Vol 198 (1) ◽  
pp. 75-83 ◽  
Author(s):  
Victor A. Zammit

1. The concentrations of malonyl-CoA, glycerol 3-phosphate, non-esterified carnitine, acid-soluble and acid-insoluble acylcarnitines, acetoacetate, 3-hydroxybutyrate and acid-insoluble acyl-CoA were measured in rapidly-frozen liver samples from fed or starved (24h) virgin, pregnant (19–20 days), lactating (2, 10–12 and 18–20 days) and weaned (for 24h, on 10th day of lactation) rats. The activities of total and N-ethylmaleimide-sensitive and -insensitive glycerophosphate acyltransferase (acyl-CoA:sn-glycerol 3-phosphate O-acyltransferase; EC 2.3.1.15) were also measured. 2. The concentration of malonyl-CoA was significantly higher in liver of fed pregnant, mid- and late-lactating rats than in liver of fed virgin rats. After starvation for 24h hepatic malonyl-CoA concentrations were higher in mid-lactating rats and lower in pregnant and weaned rats than in virgin animals. 3. After starvation for 24h the hepatic concentrations of glycerol 3-phosphate, ketone bodies, acid-soluble acylcarnitines and the value for the [3-hydroxybutyrate]/[acetoacetate] ratio were all highest in pregnant rats, intermediate in virgin, 2-day lactating and weaned animals and lowest in mid- and late-lactating rats. The concentrations of acid-insoluble acylcarnitines also increased most in pregnant rats, after starvation. The concentration of acid-insoluble acyl-CoA increased equally after starvation in virgin and pregnant animals but did not increase significantly in all other animals studied. 4. The total concentration of carnitine was similar in livers of fed virgin, pregnant and 2-day lactating animals but fell markedly by the 10th day of lactation and remained low in late-lactating animals. The concentration of non-esterified carnitine followed the same pattern. After starvation for 24h the hepatic concentration of non-esterified carnitine decreased significantly in virgin, pregnant and 2-day lactating animals, but remained unchanged in mid- and late-lactating or weaned animals. 5. The activities of N-ethylmaleimide-sensitive and -insensitive glycerophosphate acyltransferase both increased significantly in livers of mid-lactating animals. After starvation for 24h the activity of the N-ethylmaleimide-insensitive O-acyltransferase decreased in livers of virgin, pregnant and mid-lactating animals, whereas the activity of the N-ethylmaleimide-sensitive O-acyltransferase was unchanged in virgin animals but decreased markedly in livers of pregnant and lactating rats. 6. The results are discussed in relation to the importance of different metabolic parameters in the regulation of long-chain acyl-CoA metabolism in the liver.


2002 ◽  
Vol 129 (4) ◽  
pp. 1710-1722 ◽  
Author(s):  
Jay M. Shockey ◽  
Martin S. Fulda ◽  
John A. Browse

2011 ◽  
Vol 30 (3) ◽  
pp. 367-376 ◽  
Author(s):  
Fumiyo Kasuya ◽  
Yasushi Miwa ◽  
Maya Kazumi ◽  
Hiroyuki Inoue ◽  
Hiroyuki Ohta

Multiple changes in metabolic levels could be useful for understanding physiological toxicity. To explore further risk factors for the convulsions induced by the interaction of nonsteroidal anti-inflammatory and new quinolone antimicrobial drugs, the effect of sparfloxacin, enoxacin, and felbinac on fatty acid metabolism and glucose concentrations in the liver, brain, and blood of rats was investigated. The levels of long-chain acyl-CoAs (C18:1 and C20:4) in the liver and brain were decreased at the onset of convulsions induced by the coadministration of enoxacin with felbinac. Then, glucose concentrations in the liver and blood were decreased, whereas they were increased in a dose-dependant manner in the brain. However, the formation of acyl-CoAs and glucose levels in the liver, brain, and blood was not significantly influenced by enoxacin, felbinac, and sparfloxacin alone, respectively. The disturbance of both fatty acid metabolism and glucose levels might be associated with the increased susceptibility to convulsions, which may contribute to further understanding of the toxic effects associated with these drugs.


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