scholarly journals Gene expression of enzymes regulating ketogenesis and fatty acid metabolism in regenerating rat liver

1994 ◽  
Vol 299 (1) ◽  
pp. 65-69 ◽  
Author(s):  
G Asins ◽  
J L Rosa ◽  
D Serra ◽  
G Gil-Gómez ◽  
J Ayté ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Surgical Stress ◽  
Control Point ◽  
Diabetic Rats ◽  
Carnitine Palmitoyltransferase ◽  
Mrna Levels ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I ◽  
Carnitine Palmitoyltransferase Ii

Levels of mRNA for mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase, carnitine palmitoyltransferase I (CPT I) and carnitine palmitoyltransferase II (CPT II), fatty acid synthase (FAS) and actin were analysed during liver regeneration. mRNA levels for mitochondrial HMG-CoA synthase decreased rapidly, reaching a minimum 12 h after partial hepatectomy and returning to normal at 24-36 h. In contrast, CPT I, CPT II and FAS mRNAs increased throughout the period examined. Expression of actin increased significantly during regeneration. Levels of mRNA for mitochondrial HMG-CoA synthase also decreased as a result of surgical stress, although the effect of hepatectomy was much greater. We determined the levels of mitochondrial HMG-CoA synthase using specific antibodies. The amount of protein rapidly decreased, although less markedly than the corresponding mRNA levels. These results show that the decrease described in ketogenesis in partially hepatectomized rats correlated with the decrease in the expression of mitochondrial HMG-CoA synthase, suggesting that this enzyme may also be a control point in ketogenesis in the regenerating liver, as it is in normal and diabetic rats.

Carnitine palmitoyltransferase I control of acetogenesis, the major pathway of fatty acid β-oxidation in liver of neonatal swine

2010 ◽  
Vol 298 (5) ◽  
pp. R1435-R1443 ◽  
Author(s):  
Xi Lin ◽  
Kwanseob Shim ◽  
Jack Odle
Keyword(s):  
Fatty Acid ◽  
Ketone Bodies ◽  
Carnitine Palmitoyltransferase ◽  
Acid Oxidation ◽  
Major Pathway ◽  
Malonyl Coa ◽  
Suckling Piglets ◽  
Carnitine Palmitoyltransferase I ◽  
Newborn Pigs ◽  
Cpt I

To examine the regulation of hepatic acetogenesis in neonatal swine, carnitine palmitoyltransferase I (CPT I) activity was measured in the presence of varying palmitoyl-CoA (substrate) and malonyl-CoA (inhibitor) concentrations, and [1-14C]-palmitate oxidation was simultaneously measured. Accumulation rates of 14C-labeled acetate, ketone bodies, and citric acid cycle intermediates within the acid-soluble products were determined using radio-HPLC. Measurements were conducted in mitochondria isolated from newborn, 24-h (fed or fasted), and 5-mo-old pigs. Acetate rather than ketone bodies was the predominant radiolabeled product, and its production increased twofold with increasing fatty acid oxidation during the first 24-h suckling period. The rate of acetogenesis was directly proportional to CPT I activity. The high activity of CPT I in 24-h-suckling piglets was not attributable to an increase in CPT I gene expression, but rather to a large decrease in the sensitivity of CPT I to malonyl-CoA inhibition, which offset a developmental decrease in affinity of CPT I for palmitoyl-CoA. Specifically, the IC50 for malonyl-CoA inhibition and Km value for palmitoyl-CoA measured in 24-h-suckling pigs were 1.8- and 2.7-fold higher than measured in newborn pigs. The addition of anaplerotic carbon from malate (10 mM) significantly reduced 14C accumulation in acetate ( P < 0.003); moreover, the reduction was much greater in newborn (80%) than in 24-h-fed (72%) and 5-mo-old pigs (55%). The results demonstrate that acetate is the primary product of hepatic mitochondrial β-oxidation in Sus scrofa and that regulation during early development is mediated primarily via kinetic modulation of CPT I.

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.

Myocardial carnitine palmitoyltransferase I expression and long-chain fatty acid oxidation in fetal and newborn lambs

2004 ◽  
Vol 286 (6) ◽  
pp. H2243-H2248 ◽  
Author(s):  
Beatrijs Bartelds ◽  
Janny Takens ◽  
Gioia B. Smid ◽  
Victor A. Zammit ◽  
Carina Prip-Buus ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Left Ventricular ◽  
Chain Fatty Acid ◽  
Carnitine Palmitoyltransferase ◽  
Long Chain Fatty Acid ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I ◽  
Long Chain

Carnitine palmitoyltransferase I (CPT I) catalyzes the conversion of acyl-CoA to acylcarnitine at the outer mitochondrial membrane and is a key enzyme in the control of long-chain fatty acid (LC-FA) oxidation. Because myocardial LC-FA oxidation increases dramatically after birth, we determined the extent to which CPT I expression contributes to these changes in the perinatal lamb. We measured the steady-state level of transcripts of the CPT1A and CPT1B genes, which encode the liver (L-CPT I) and muscle CPT I (M-CPT I) isoforms, respectively, as well as the amount of these proteins, their total activity, and the amount of carnitine in left ventricular tissue from fetal and newborn lambs. We compared these data with previously obtained myocardial FA oxidation rates in vivo in the same model. The results showed that CPT1B was already expressed before birth and that total CPT I expression transiently increased after birth. The protein level of M-CPT I was high throughout development, whereas that of L-CPT I was only transiently upregulated in the first week after birth. The total CPT I activity in vitro also increased after birth. However, the increase in myocardial FA oxidation measured in vivo (112-fold) by far exceeded the increase in gene expression (2.2-fold), protein amount (1.1-fold), and enzyme activity (1.2-fold) in vitro. In conclusion, these results stress the importance of substrate supply per se in the postnatal increase in myocardial FA oxidation. M-CPT I is expressed throughout perinatal development, making it a primary target for metabolic modulation of myocardial FA oxidation.

Evidence of a malonyl-CoA-insensitive carnitine palmitoyltransferase I activity in red skeletal muscle

2002 ◽  
Vol 282 (5) ◽  
pp. E1014-E1022 ◽  
Author(s):  
Jong-Yeon Kim ◽  
Timothy R. Koves ◽  
Geng-Sheng Yu ◽  
Tod Gulick ◽  
Ronald N. Cortright ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Splice Variants ◽  
Fiber Type ◽  
Carnitine Palmitoyltransferase ◽  
Acid Oxidation ◽  
Palmitate Oxidation ◽  
Oxidation Rates ◽  
Malonyl Coa ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I

Carnitine palmitoyltransferase I (CPT I), which is expressed as two distinct isoforms in liver (α) and muscle (β), catalyzes the rate-limiting step in the transport of fatty acid into the mitochondria. Malonyl-CoA, a potent inhibitor of CPT I, is considered a key regulator of fatty acid oxidation in both tissues. Still unanswered is how muscle β-oxidation proceeds despite malonyl-CoA concentrations that exceed the IC50 for CPT Iβ. We evaluated malonyl-CoA-suppressible [14C]palmitate oxidation and CPT I activity in homogenates of red (RG) and white (WG) gastrocnemius, soleus (SOL), and extensor digitorum longus (EDL) muscles. Adding 10 μM malonyl-CoA inhibited palmitate oxidation by 29, 39, 60, and 89% in RG, SOL, EDL, and WG, respectively. Thus malonyl-CoA resistance, which correlated strongly (0.678) with absolute oxidation rates (RG > SOL > EDL > WG), was greater in red than in white muscles. Similarly, malonyl-CoA-resistant palmitate oxidation and CPT I activity were greater in mitochondria from RG compared with WG. Ribonuclease protection assays were performed to evaluate whether our data might be explained by differential expression of CPT I splice variants. We detected the presence of two CPT Iβ splice variants that were more abundant in red compared with white muscle, but the relative expression of the two mRNA species was unrelated to malonyl-CoA resistance. These results provide evidence of a malonyl-CoA-insensitive CPT I activity in red muscle, suggesting fiber type-specific expression of distinct CPT I isoforms and/or posttranslational modulations that have yet to be elucidated.

scholarly journals Catechins and Caffeine Inhibit Fat Accumulation in Mice through the Improvement of Hepatic Lipid Metabolism

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Chikako Sugiura ◽  
Shiho Nishimatsu ◽  
Tatsuya Moriyama ◽  
Sayaka Ozasa ◽  
Teruo Kawada ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Epigallocatechin Gallate ◽  
Acid Synthesis ◽  
Control Group ◽  
Mrna Levels ◽  
Fat Accumulation ◽  
Treatment Groups ◽  
Fas Mrna ◽  
Carnitine Palmitoyltransferase Ii

To elucidate the inhibiting mechanisms of fat accumulation by catechins, caffeine, and epigallocatechin gallate (EGCG), ICR mice were fed diets containing either 0.3% catechins or 0.1% EGCG and/or 0.05% caffeine for 4 weeks. After the feeding, intraperitoneal adipose tissues weights were significantly lower in the caffeine, catechins + caffeine, and EGCG + caffeine groups compared to controls. Hepatic fatty acid synthase (FAS) activity in the catechins + caffeine group was significantly lower, and the activities of acyl-CoA oxidase (ACO) and carnitine palmitoyltransferase-II (CPT-II) were significantly higher, compared to the control group. However, these activities were not observed in the other groups. FAS mRNA expression levels in the catechins + caffeine group were significantly lower than in the control group. ACO and CPT-II mRNA levels were not different among all of the treatment groups. These findings indicate that the inhibitory effects of fat accumulation via a combination of catechins, EGCG, or caffeine were stronger collectively than by either catechins, EGCG, or caffeine alone. Moreover, it was demonstrated that the combination of catechins and caffeine induced inhibition of fat accumulation by suppression of fatty acid synthesis and upregulation of the enzymatic activities involved inβ-oxidation of fatty acid in the liver, but this result was not observed by combination of EGCG and caffeine.

scholarly journals Etomoxir-induced partial carnitine palmitoyltransferase-I (CPT-I) inhibition in vivo does not alter cardiac long-chain fatty acid uptake and oxidation rates

2009 ◽  
Vol 419 (2) ◽  
pp. 447-455 ◽  
Author(s):  
Joost J. F. P. Luiken ◽  
Hanneke E. C. Niessen ◽  
Susan L. M. Coort ◽  
Nicole Hoebers ◽  
Will A. Coumans ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Chain Fatty Acid ◽  
Carnitine Palmitoyltransferase ◽  
Acid Uptake ◽  
Long Chain Fatty Acid ◽  
Fatty Acid Binding ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I ◽  
Lcfa Uptake ◽  
Long Chain

Although CPT-I (carnitine palmitoyltransferase-I) is generally regarded to present a major rate-controlling site in mitochondrial β-oxidation, it is incompletely understood whether CPT-I is rate-limiting in the overall LCFA (long-chain fatty acid) flux in the heart. Another important site of regulation of the LCFA flux in the heart is trans-sarcolemmal LCFA transport facilitated by CD36 and FABPpm (plasma membrane fatty acid-binding protein). Therefore, we explored to what extent a chronic pharmacological blockade of the LCFA flux at the level of mitochondrial entry of LCFA-CoA would affect sarcolemmal LCFA uptake. Rats were injected daily with saline or etomoxir, a specific CPT-I inhibitor, for 8 days at 20 mg/kg of body mass. Etomoxir-treated rats displayed a 44% reduced cardiac CPT-I activity. Sarcolemmal contents of CD36 and FABPpm, as well as the LCFA transport capacity, were not altered in the hearts of etomoxir-treated versus control rats. Furthermore, rates of LCFA uptake and oxidation, and glucose uptake by cardiac myocytes from etomoxir-treated rats were not different from control rats, neither under basal nor under acutely induced maximal metabolic demands. Finally, hearts from etomoxir-treated rats did not display triacylglycerol accumulation. Therefore CPT-I appears not to present a major rate-controlling site in total cardiac LCFA flux. It is likely that sarcolemmal LCFA entry rather than mitochondrial LCFA-CoA entry is a promising target for normalizing LCFA flux in cardiac metabolic diseases.

scholarly journals Muscle Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Conceptual Approach

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1784
Author(s):  
Pushpa Raj Joshi ◽  
Stephan Zierz
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Carnitine Palmitoyltransferase ◽  
Tween 20 ◽  
Acid Oxidation ◽  
Malonyl Coa ◽  
Cpt I ◽  
Carnitine Palmitoyltransferase Ii ◽  
Triton X ◽  
Cpt Ii Deficiency

Carnitine palmitoyltransferase (CPT) catalyzes the transfer of long- and medium-chain fatty acids from cytoplasm into mitochondria, where oxidation of fatty acids takes place. Deficiency of CPT enzyme is associated with rare diseases of fatty acid metabolism. CPT is present in two subforms: CPT I at the outer mitochondrial membrane and carnitine palmitoyltransferase II (CPT II) inside the mitochondria. Deficiency of CPT II results in the most common inherited disorder of long-chain fatty acid oxidation affecting skeletal muscle. There is a lethal neonatal form, a severe infantile hepato-cardio-muscular form, and a rather mild myopathic form characterized by exercise-induced myalgia, weakness, and myoglobinuria. Total CPT activity (CPT I + CPT II) in muscles of CPT II-deficient patients is generally normal. Nevertheless, in some patients, not detectable to reduced total activities are also reported. CPT II protein is also shown in normal concentration in patients with normal CPT enzymatic activity. However, residual CPT II shows abnormal inhibition sensitivity towards malonyl-CoA, Triton X-100 and fatty acid metabolites in patients. Genetic studies have identified a common p.Ser113Leu mutation in the muscle form along with around 100 different rare mutations. The biochemical consequences of these mutations have been controversial. Hypotheses include lack of enzymatically active protein, partial enzyme deficiency and abnormally regulated enzyme. The recombinant enzyme experiments that we recently conducted have shown that CPT II enzyme is extremely thermoliable and is abnormally inhibited by different emulsifiers and detergents such as malonyl-CoA, palmitoyl-CoA, palmitoylcarnitine, Tween 20 and Triton X-100. Here, we present a conceptual overview on CPT II deficiency based on our own findings and on results from other studies addressing clinical, biochemical, histological, immunohistological and genetic aspects, as well as recent advancements in diagnosis and therapeutic strategies in this disorder.

scholarly journals Ketone-body metabolism after surgical stress or partial hepatectomy. Evidence for decreased ketogenesis and a site of control distal to carnitine palmitoyltransferase I

1987 ◽  
Vol 241 (2) ◽  
pp. 475-481 ◽  
Author(s):  
P S Schofield ◽  
T J French ◽  
M C Sugden
Keyword(s):  
Partial Hepatectomy ◽  
Ketone Body ◽  
Surgical Stress ◽  
Carnitine Palmitoyltransferase ◽  
Medium Chain ◽  
Medium Chain Length ◽  
Sustained Effects ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I ◽  
A Site

Rats were subjected to laparotomy, or laparotomy and partial hepatectomy, at 0-48 h before administration of water or medium-chain-length triacylglycerol, having been starved post-operatively. Functional hepatectomies were performed at intervals after the intragastric load. Blood ketone-body concentrations after medium-chain triacylglycerol administration and/or functional hepatectomy of these rats were compared with values obtained in starved control rats. Decreased ketonaemia in response to medium-chain triacylglycerol was observed for up to 48 h after partial hepatectomy and at 1 and 2 h after laparotomy, but not at 24 or 48 h after laparotomy. Rates of ketone-body clearance after functional hepatectomy were unaffected by prior laparotomy or partial hepatectomy. Ketonaemia after medium-chain-triacylglycerol administration was only partially blocked by inhibition of CPT I (carnitine palmitoyltransferase I). The results demonstrate sustained effects of partial hepatectomy and short-term effects of surgical stress to decrease ketonaemia via inhibition of ketogenesis at site(s) distal to CPT I.

Overexpression of carnitine palmitoyltransferase I in skeletal muscle in vivo increases fatty acid oxidation and reduces triacylglycerol esterification

2007 ◽  
Vol 292 (4) ◽  
pp. E1231-E1237 ◽  
Author(s):  
Clinton R. Bruce ◽  
Camilla Brolin ◽  
Nigel Turner ◽  
Mark E. Cleasby ◽  
Feike R. van der Leij ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Carnitine Palmitoyltransferase ◽  
Acid Oxidation ◽  
Malonyl Coa ◽  
Carnitine Palmitoyltransferase I ◽  
Edl Muscle ◽  
Cpt I ◽  
The Right

A key regulatory point in the control of fatty acid (FA) oxidation is thought to be transport of FAs across the mitochondrial membrane by carnitine palmitoyltransferase I (CPT I). To investigate the role of CPT I in FA metabolism, we used in vivo electrotransfer (IVE) to locally overexpress CPT I in muscle of rodents. A vector expressing the human muscle isoform of CPT I was electrotransferred into the right lateral muscles of the distal hindlimb [tibialis cranialis (TC) and extensor digitorum longus (EDL)] of rats, and a control vector expressing GFP was electrotransferred into the left muscles. Initial studies showed that CPT I protein expression peaked 7 days after IVE (+104%, P < 0.01). This was associated with an increase in maximal CPT I activity (+30%, P < 0.001) and a similar increase in palmitoyl-CoA oxidation (+24%; P < 0.001) in isolated mitochondria from the TC. Importantly, oxidation of the medium-chain FA octanoyl-CoA and CPT I sensitivity to inhibition by malonyl-CoA were not altered by CPT I overexpression. FA oxidation in isolated EDL muscle strips was increased with CPT I overexpression (+28%, P < 0.01), whereas FA incorporation into the muscle triacylglycerol (TAG) pool was reduced (−17%, P < 0.01). As a result, intramyocellular TAG content was decreased with CPT I overexpression in both the TC (−25%, P < 0.05) and the EDL (−45%, P < 0.05). These studies demonstrate that acute overexpression of CPT I in muscle leads to a repartitioning of FAs away from esterification and toward oxidation and highlight the importance of CPT I in regulating muscle FA metabolism.

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