Cytosolic reverse CrAT activity in cardiac tissue: potential importance for fuel selection

2018 ◽  
Vol 475 (7) ◽  
pp. 1267-1269
Author(s):  
Heather L. Petrick ◽  
Graham P. Holloway
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Cardiac Tissue ◽  
Reverse Direction ◽  
Acid Oxidation ◽  
Substrate Selection ◽  
Reciprocal Regulation ◽  
Rate Limiting Step ◽  
Biochemical Journal ◽  
Cpt I

The movement of lipids across mitochondrial membranes represents a rate-limiting step in fatty acid oxidation within the heart. A key regulatory point in this process is flux through carnitine palmitoyltransferase-I (CPT-I), an enzyme located on the outer mitochondrial membrane. Malonyl-CoA (M-CoA) is a naturally occurring inhibitor of CPT-I; therefore, the abundance of M-CoA has long been considered a major regulator of fatty acid oxidation. A recent paper published in the Biochemical Journal by Altamimi et al. (Biochem. J. (2018) 475, 959–976) provides evidence for a novel mechanism to produce M-CoA. Specifically, these authors identified carnitine acetyltransferase within the cytosol and further show that flux in the reverse direction forms acetyl-CoA, which is the necessary substrate for the subsequent synthesis of M-CoA. The elegant study design and intriguing data presented by Altamimi et al. provide further insights into the reciprocal regulation of substrate selection within the heart, with implications for fuel utilization and the development of cardiac diseases.

scholarly journals The role of changes in the sensitivity of hepatic mitochondrial overt carnitine palmitoyltransferase in determining the onset of the ketosis of starvation in the rat

1996 ◽  
Vol 318 (3) ◽  
pp. 767-770 ◽  
Author(s):  
Lesley DRYNAN ◽  
Patti A. QUANT ◽  
Victor A. ZAMMIT
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Time Course ◽  
Ketone Body ◽  
Serum Insulin ◽  
Carnitine Palmitoyltransferase ◽  
Acid Oxidation ◽  
Malonyl Coa ◽  
Cpt I ◽  
Body Concentration

The relationships between the increase in blood ketone-body concentrations and several parameters that can potentially influence the rate of hepatic fatty acid oxidation were studied during progressive starvation (up to 24 h) in the rat in order to discover whether the sensitivity of mitochondrial overt carnitine palmitoyltransferase (CPT I) to malonyl-CoA plays an important part in determining the intrahepatic potential for fatty acid oxidation during the onset of ketogenic conditions. A rapid increase in blood ketone-body concentration occurred between 12 and 16 h of starvation, several hours after the marked fall in hepatic malonyl-CoA and in serum insulin concentrations and doubling of plasma non-esterfied fatty acid (NEFA) concentration. Consequently, both the changes in hepatic malonyl-CoA and serum NEFA preceded the increase in blood ketone-body concentration by several hours. The maximal activity of CPT I increased gradually throughout the 24 h period of starvation, but the increases did not become significant before 18 h of starvation. By contrast, the sensitivity of CPT I to malonyl-CoA and the increase in blood ketone-body concentration followed an identical time course, demonstrating the central importance of this parameter in determining the ketogenic response of the liver to the onset of the starved state.

scholarly journals Increase in fatty acid oxidation in calvaria cells cultured with diphosphonates

1981 ◽  
Vol 196 (1) ◽  
pp. 237-245 ◽  
Author(s):  
R Felix ◽  
H Fleisch
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Lactate Production ◽  
Water Soluble ◽  
Acid Oxidation ◽  
Palmitate Oxidation ◽  
Rate Limiting Step ◽  
Inhibition Of Glycolysis ◽  
Inhibitor Of Protein Synthesis ◽  
Cells Cultured

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.

scholarly journals Evidence that the sensitivity of carnitine palmitoyltransferase I to inhibition by malonyl-CoA is an important site of regulation of hepatic fatty acid oxidation in the fetal and newborn rabbit. Perinatal development and effects of pancreatic hormones in cultured rabbit hepatocytes

1990 ◽  
Vol 269 (2) ◽  
pp. 409-415 ◽  
Author(s):  
C Prip-Buus ◽  
J P Pegorier ◽  
P H Duee ◽  
C Kohl ◽  
J Girard
Keyword(s):  
Fatty Acid ◽  
Cyclic Amp ◽  
Fatty Acid Oxidation ◽  
Carnitine Palmitoyltransferase ◽  
Acid Oxidation ◽  
Fetal Hepatocytes ◽  
Malonyl Coa ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I ◽  
Hepatic Fatty Acid Oxidation

The temporal changes in oleate oxidation, lipogenesis, malonyl-CoA concentration and sensitivity of carnitine palmitoyltransferase I (CPT 1) to malonyl-CoA inhibition were studied in isolated rabbit hepatocytes and mitochondria as a function of time after birth of the animal or time in culture after exposure to glucagon, cyclic AMP or insulin. (1) Oleate oxidation was very low during the first 6 h after birth, whereas lipogenesis rate and malonyl-CoA concentration decreased rapidly during this period to reach levels as low as those found in 24-h-old newborns that show active oleate oxidation. (2) The changes in the activity of CPT I and the IC50 (concn. causing 50% inhibition) for malonyl-CoA paralleled those of oleate oxidation. (3) In cultured fetal hepatocytes, the addition of glucagon or cyclic AMP reproduced the changes that occur spontaneously after birth. A 12 h exposure to glucagon or cyclic AMP was sufficient to inhibit lipogenesis totally and to cause a decrease in malonyl-CoA concentration, but a 24 h exposure was required to induce oleate oxidation. (4) The induction of oleate oxidation by glucagon or cyclic AMP is triggered by the fall in the malonyl-CoA sensitivity of CPT I. (5) In cultured hepatocytes from 24 h-old newborns, the addition of insulin inhibits no more than 30% of the high oleate oxidation, whereas it stimulates lipogenesis and increases malonyl-CoA concentration by 4-fold more than in fetal cells (no oleate oxidation). This poor effect of insulin on oleate oxidation seems to be due to the inability of the hormone to increase the sensitivity of CPT I sufficiently. Altogether, these results suggest that the malonyl-CoA sensitivity of CPT I is the major site of regulation during the induction of fatty acid oxidation in the fetal rabbit liver.

A Case of Mistaken Identity

2005 ◽  
Vol 288 (1) ◽  
pp. H448-H448 ◽  
Author(s):  
Andreas Stahl
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Early Development ◽  
Mammalian Species ◽  
Expression Patterns ◽  
Acid Oxidation ◽  
Published Data ◽  
Acid Uptake ◽  
Expression Of Genes ◽  
Cpt I

The heart is a unique organ that can use several fuels for energy production. During development, the heart undergoes changes in fuel supply, and it must be able to respond to these changes. We have examined changes in the expression of several genes that regulate fuel transport and metabolism in rat hearts during early development. At birth, there was increased expression of fatty acid transporters and enzymes of fatty acid metabolism that allow fatty acids to become the major source of energy for cardiac muscle during the first 2 wk of life. At the same time, expression of genes that control glucose transport and oxidation was downregulated. After 2 wk, expression of genes for glucose uptake and oxidation was increased, and expression of genes for fatty acid uptake and utilization was decreased. Expression of carnitine palmitoyltransferase I (CPT I) isoforms during development was different from published data obtained from rabbit hearts. CPT Iα and Iβ isoforms were both highly expressed in hearts before birth, and both increased further at birth. Only after the second week did CPT Iα expression decrease appreciably below the level of CPT Iβ expression. These results represent another example of different expression patterns of CPT I isoforms among various mammalian species. In rats, changes in gene expression followed nutrient availability during development and may render cardiac fatty acid oxidation less sensitive to factors that influence malonyl-CoA content (e.g., fluctuations in glucose concentration) and thereby favor fatty acid oxidation as an energy source for cardiomyocytes in early development.

Development of independent ingestive responding to blockade of fatty acid oxidation in rats

1997 ◽  
Vol 273 (5) ◽  
pp. R1649-R1656 ◽  
Author(s):  
Susan E. Swithers
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
The Other ◽  
Acid Oxidation ◽  
Low Doses ◽  
Rat Pups ◽  
Carnitine Palmitoyltransferase I ◽  
Metabolic Signal ◽  
Cpt I ◽  
Acyl Coenzyme A

The present studies examined the development of ingestive responsiveness to blockade of fatty acid oxidation in rat pups using 2-mercaptoacetate (MA), an inhibitor of mitochondrial acyl-coenzyme A dehydrogenases, or methyl palmoxirate (MP), an inhibitor of carnitine palmitoyltransferase I (CPT-I). Rat pups aged 6, 9, 12, or 15 days of age received an intraperitoneal injection of 0, 100, 200, 400, or 800 μmol/kg MA, and intake of a commercial half-and-half or 15% glucose diet from the floor of test containers was assessed in a 30-min test beginning 1 h after administration of MA. The results demonstrate that, although no dose of MA affected intake of either diet in pups 9 days or younger, low doses of MA increased intake and the highest dose suppressed intake of both diets in pups 12 days of age or older. Physiological measurements indicated that levels of β-hydroxybutyrate were significantly lower following doses of 400 or 800 μmol/kg MA in 9-, 12-, and 15-day-old pups and that gastric emptying was inhibited in 12 and 15 day olds by 800 μmol/kg MA. Intake of a commercial half-and-half diet from the floor of test containers was also assessed in 12- to 18-day-old rat pups 6.5 h after they received a gavage load of 0, 1.25, 2.5, 5, or 10 mg/kg MP. Unlike MA, MP did not increase intake of a commercial half-and-half diet in rat pups 12 or 15–18 days of age; instead, the highest dose of MP suppressed intake in 15- to 18-day-old pups. The failure of MP to enhance intake in pups at the ages tested is likely related to composition of dam’s milk; rat milk is high in medium-chain fatty acids that do not require CPT-I for entry into mitochondria. Thus it is likely that MP does not significantly block fatty acid oxidation in pups at the ages tested. On the other hand, blockade of fatty acid oxidation produced by MA significantly affects intake by 12 days of age, suggesting it may be the first metabolic signal that influences intake in rat pups.

scholarly journals Adenovirus-mediated overexpression of liver carnitine palmitoyltransferase I in INS1E cells: effects on cell metabolism and insulin secretion

2002 ◽  
Vol 364 (1) ◽  
pp. 219-226 ◽  
Author(s):  
Blanca RUBÍ ◽  
Peter A. ANTINOZZI ◽  
Laura HERRERO ◽  
Hisamitsu ISHIHARA ◽  
Guillermina ASINS ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fold Increase ◽  
Acid Oxidation ◽  
Β Cells ◽  
Β Cell ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I

Lipid metabolism in the β-cell is critical for the regulation of insulin secretion. Pancreatic β-cells chronically exposed to fatty acids show higher carnitine palmitoyltransferase I (CPT I) protein levels, higher palmitate oxidation rates and an altered insulin response to glucose. We examined the effect of increasing CPT I levels on insulin secretion in cultured β-cells. We prepared a recombinant adenovirus containing the cDNA for the rat liver isoform of CPT I. The overexpression of CPT I in INS1E cells caused a more than a 5-fold increase in the levels of CPT I protein (detected by Western blotting), a 6-fold increase in the CPT activity, and an increase in fatty acid oxidation at 2.5mM glucose (1.7-fold) and 15mM glucose (3.1-fold). Insulin secretion was stimulated in control cells by 15mM glucose or 30mM KCl. INS1E cells overexpressing CPT I showed lower insulin secretion on stimulation with 15mM glucose (−40%; P<0.05). This decrease depended on CPT I activity, since the presence of etomoxir, a specific inhibitor of CPT I, in the preincubation medium normalized the CPT I activity, the fatty-acid oxidation rate and the insulin secretion in response to glucose. Exogenous palmitate (0.25mM) rescued glucose-stimulated insulin secretion (GSIS) in CPT I-overexpressing cells, indicating that the mechanism of impaired GSIS was through the depletion of a critical lipid. Depolarizing the cells with KCl or intermediary glucose concentrations (7.5mM) elicited similar insulin secretion in control cells and cells overexpressing CPT I. Glucose-induced ATP increase, glucose metabolism and the triacylglycerol content remained unchanged. These results provide further evidence that CPT I activity regulates insulin secretion in the β-cell. They also indicate that up-regulation of CPT I contributes to the loss of response to high glucose in β-cells exposed to fatty acids.

Pitfalls in interpretation of experiments using etomoxir as an inhibitor of CPT I-dependent fatty acid oxidation

2000 ◽  
Vol 50 ◽  
pp. 188
Author(s):  
Victoria Esser ◽  
Shohrae Hajibashi ◽  
Brent E Stevenson ◽  
Mark Luiao ◽  
J.Denis McGarry
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Cpt I

The role of chicken ovalbumin upstream promoter transcription factor II in the regulation of hepatic fatty acid oxidation and gluconeogenesis in newborn mice

2015 ◽  
Vol 308 (10) ◽  
pp. E868-E878 ◽  
Author(s):  
Julien Planchais ◽  
Marie Boutant ◽  
Véronique Fauveau ◽  
Lou Dan Qing ◽  
Lina Sabra-Makke ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Newborn Mice ◽  
Factor Ii ◽  
Upstream Promoter ◽  
Cpt I ◽  
Chicken Ovalbumin

Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) is an orphan nuclear receptor involved in the control of numerous functions in various organs (organogenesis, differentiation, metabolic homeostasis, etc.). The aim of the present work was to characterize the regulation and contribution of COUP-TFII in the control of hepatic fatty acid and glucose metabolisms in newborn mice. Our data show that postnatal increase in COUP-TFII mRNA levels is enhanced by glucagon (via cAMP) and PPARα. To characterize COUP-TFII function in the liver of suckling mice, we used a functional (dominant negative form; COUP-TFII-DN) and a genetic (shRNA) approach. Adenoviral COUP-TFII-DN injection induces a profound hypoglycemia due to the inhibition of gluconeogenesis and fatty acid oxidation secondarily to reduced PEPCK, Gl-6-Pase, CPT I, and mHMG-CoA synthase gene expression. Using the crossover plot technique, we show that gluconeogenesis is inhibited at two different levels: 1) pyruvate carboxylation and 2) trioses phosphate synthesis. This could result from a decreased availability in fatty acid oxidation arising cofactors such as acetyl-CoA and reduced equivalents. Similar results are observed using the shRNA approach. Indeed, when fatty acid oxidation is rescued in response to Wy-14643-induced PPARα target genes (CPT I and mHMG-CoA synthase), blood glucose is normalized in COUP-TFII-DN mice. In conclusion, this work demonstrates that postnatal increase in hepatic COUP-TFII gene expression is involved in the regulation of liver fatty acid oxidation, which in turn sustains an active hepatic gluconeogenesis that is essential to maintain an appropriate blood glucose level required for newborn mice survival.

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