Alterations to mitochondrial fatty-acid use in skeletal muscle after chronic exposure to hypoxia depend on metabolic phenotype

2017 ◽  
Vol 122 (3) ◽  
pp. 666-674 ◽  
Author(s):  
Alexandra Malgoyre ◽  
Clovis Chabert ◽  
Julia Tonini ◽  
Nathalie Koulmann ◽  
Xavier Bigard ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Caloric Restriction ◽  
Respiratory Exchange Ratio ◽  
Chronic Hypoxia ◽  
Metabolic Phenotype ◽  
Palmitoyl Carnitine ◽  
Low Concentrations ◽  
Mitochondrial Fatty Acid ◽  
Fuel Preference ◽  
Long Chain

We investigated the effects of chronic hypoxia on the maximal use of and sensitivity of mitochondria to different substrates in rat slow-oxidative (soleus, SOL) and fast-glycolytic (extensor digitorum longus, EDL) muscles. We studied mitochondrial respiration in situ in permeabilized myofibers, using pyruvate, octanoate, palmitoyl-carnitine (PC), or palmitoyl-coenzyme A (PCoA). The hypophagia induced by hypoxia may also alter metabolism. Therefore, we used a group of pair-fed rats (reproducing the same caloric restriction, as observed in hypoxic animals), in addition to the normoxic control fed ad libitum. The resting respiratory exchange ratio decreased after 21 days of exposure to hypobaric hypoxia (simulated elevation of 5,500 m). The respiration supported by pyruvate and octanoate were unaffected. In contrast, the maximal oxidative respiratory rate for PCoA, the transport of which depends on carnitine palmitoyltransferase 1 (CPT-1), decreased in the rapid-glycolytic EDL and increased in the slow-oxidative SOL, although hypoxia improved affinity for this substrate in both muscle types. PC and PCoA were oxidized similarly in normoxic EDL, whereas chronic hypoxia limited transport at the CPT-1 step in this muscle. The effects of hypoxia were mediated by caloric restriction in the SOL and by hypoxia itself in the EDL. We conclude that improvements in mitochondrial affinity for PCoA, a physiological long-chain fatty acid, would facilitate fatty-acid use at rest after chronic hypoxia independently of quantitative alterations of mitochondria. Conversely, decreasing the maximal oxidation of PCoA in fast-glycolytic muscles would limit fatty-acid use during exercise. NEW & NOTEWORTHY Affinity for low concentrations of long-chain fatty acids (LCFA) in mitochondria skeletal muscles increases after chronic hypoxia. Combined with a lower respiratory exchange ratio, this suggests facility for fatty acid utilization at rest. This fuel preference is related to caloric restriction in oxidative muscle and to hypoxia in glycolytic one. In contrast, maximal oxidation for LCFA is decreased by chronic hypoxia in glycolytic muscle and can explain glucose dependence at exercise.

scholarly journals Nrf2 affects the efficiency of mitochondrial fatty acid oxidation

2014 ◽  
Vol 457 (3) ◽  
pp. 415-424 ◽  
Author(s):  
Marthe H. R. Ludtmann ◽  
Plamena R. Angelova ◽  
Ying Zhang ◽  
Andrey Y. Abramov ◽  
Albena T. Dinkova-Kostova
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Saturated Fatty Acids ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Atp Production ◽  
Mitochondrial Fatty Acid ◽  
Mitochondrial Oxidation ◽  
Long Chain

Transcription factor Nrf2 affects fatty acid oxidation; the mitochondrial oxidation of long-chain (palmitic) and short-chain (hexanoic) saturated fatty acids is depressed in the absence of Nrf2 and accelerated when Nrf2 is constitutively activated, affecting ATP production and FADH2 utilization.

scholarly journals Determining the Bioenergetic Capacity for Fatty Acid Oxidation in the Mammalian Nervous System

2020 ◽  
Vol 40 (10) ◽  
Author(s):  
Cory J. White ◽  
Jieun Lee ◽  
Joseph Choi ◽  
Tiffany Chu ◽  
Susanna Scafidi ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Nervous System ◽  
Fatty Acid ◽  
Conditional Knockout ◽  
Mammalian Brain ◽  
Metabolic State ◽  
Peripheral Tissues ◽  
Mitochondrial Fatty Acid ◽  
The Brain ◽  
Long Chain

ABSTRACT The metabolic state of the brain can greatly impact neurologic function. Evidence of this includes the therapeutic benefit of a ketogenic diet in neurologic diseases, including epilepsy. However, brain lipid bioenergetics remain largely uncharacterized. The existence, capacity, and relevance of mitochondrial fatty acid β-oxidation (FAO) in the brain are highly controversial, with few genetic tools available to evaluate the question. We have provided evidence for the capacity of brain FAO using a pan-brain-specific conditional knockout (KO) mouse incapable of FAO due to the loss of carnitine palmitoyltransferase 2, the product of an obligate gene for FAO (CPT2B−/−). Loss of central nervous system (CNS) FAO did not result in gross neuroanatomical changes or systemic differences in metabolism. Loss of CPT2 in the brain did not result in robustly impaired behavior. We demonstrate by unbiased and targeted metabolomics that the mammalian brain oxidizes a substantial quantity of long-chain fatty acids in vitro and in vivo. Loss of CNS FAO results in robust accumulation of long-chain acylcarnitines in the brain, suggesting that the mammalian brain mobilizes fatty acids for their oxidation, irrespective of diet or metabolic state. Together, these data demonstrate that the mammalian brain oxidizes fatty acids under normal circumstances with little influence from or on peripheral tissues.

scholarly journals Drug triggered pruritus, rash, papules, and blisters – is AGEP a clash of an altered sphingolipid-metabolism and lysosomotropism of drugs accumulating in the skin?

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Markus Blaess ◽  
Lars Kaiser ◽  
Oliver Sommerfeld ◽  
René Csuk ◽  
Hans-Peter Deigner
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Uv Radiation ◽  
Sphingolipid Metabolism ◽  
Acid Oxidation ◽  
Long Chain Fatty Acids ◽  
Mitochondrial Fatty Acid ◽  
The Individual ◽  
Long Chain ◽  
Chain Fatty Acids

AbstractRash, photosensitivity, erythema multiforme, and the acute generalized exanthematous pustulosis (AGEP) are relatively uncommon adverse reactions of drugs. To date, the etiology is not well understood and individual susceptibility still remains unknown. Amiodarone, chlorpromazine, amitriptyline, and trimipramine are classified lysosomotropic as well as photosensitizing, however, they fail to trigger rash and pruritic papules in all individuals. Lysosomotropism is a common charcteristic of various drugs, but independent of individuals. There is evidence that the individual ability to respond to external oxidative stress is crosslinked with the elongation of long-chain fatty acids to very long-chain fatty acids by ELOVLs. ELOVL6 and ELOVL7 are sensitive to ROS induced depletion of cellular NADPH and insufficient regeneration via the pentose phosphate pathway and mitochondrial fatty acid oxidation. Deficiency of NADPH in presence of lysosomotropic drugs promotes the synthesis of C16-ceramide in lysosomes and may contribute to emerging pruritic papules of AGEP. However, independently from a lysosomomotropic drug, severe depletion of ATP and NAD(P)H, e.g., by UV radiation or a potent photosensitizer can trigger likewise the collapse of the lysosomal transmembrane proton gradient resulting in lysosomal C16-ceramide synthesis and pruritic papules. This kind of papules are equally present in polymorphous light eruption (PMLE/PLE) and acne aestivalis (Mallorca acne). The suggested model of a compartmentalized ceramide metabolism provides a more sophisticated explanation of cutaneous drug adverse effects and the individual sensitivity to UV radiation. Parameters such as pKa and ClogP of the triggering drug, cutaneous fatty acid profile, and ceramide profile enables new concepts in risk assessment and scoring of AGEP as well as prophylaxis outcome.

scholarly journals Medium-Chain Acyl-CoA Dehydrogenase Deficiency in an Infant with Dilated Cardiomyopathy

2009 ◽  
Vol 2009 ◽  
pp. 1-3 ◽  
Author(s):  
Marcello Marcì ◽  
Patrizia Ajovalasit
Keyword(s):  
Fatty Acid ◽  
Dilated Cardiomyopathy ◽  
Dehydrogenase Deficiency ◽  
Acid Oxidation ◽  
Inherited Disorders ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Medium Chain ◽  
Mitochondrial Fatty Acid ◽  
Chain Acyl ◽  
Long Chain

We report about an infant affected by dilated cardiomyopathy (CMP) in whom metabolic investigations evidenced medium-chain-acyl-CoA dehydrogenase deficiency (MCADD), that is one of three types of inherited disorders of mitochondrial fatty-acid -oxidation. Long-chain and very long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficits are recognized as responsible of hypertrophic or, less frequently, dilated cardiomyopathy (CMP) in childhood. Otherwise, to our knowledge, no case of MCADD associated to dilated CMP has been reported in literature.

Hepatic CPT1A Facilitates Liver-Adipose Cross-Talk via Induction of FGF21 in Mice

2021 ◽  
Author(s):  
Wei Sun ◽  
Tao Nie ◽  
Kuai Li ◽  
Wenjie Wu ◽  
Qiaoyun Long ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Chain Fatty Acid ◽  
Metabolic Phenotype ◽  
Fibroblast Growth Factor 21 ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Long Chain Fatty Acid ◽  
Molecular Events ◽  
Long Chain

<b>Background & Aims</b> <p>Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step of NAFLD. When combined with additional cellular stress, this benign status progresses to local and systemic pathological conditions such as NASH and insulin resistance. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and other peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for long chain fatty acid beta-oxidation in the liver. Here we utilise hepatocyte-specific <i>Cpt1a</i> knockout (LKO) mice to investigate the physiological consequences of abolishing hepatic long chain fatty acid metabolism.</p> <p><b>Approach & Results </b></p> <p>Compared to the wild-type (WT) littermates, high fat diet (HFD)-fed LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic ER stress, inflammation and damage. Interestingly, increased energy expenditure was observed in LKO mice, accompanied by enhanced adipose tissue browning. RNAseq analysis revealed that the peroxisome proliferator activator alpha (PPARα)- fibroblast growth factor 21 (FGF21) axis was activated in liver of LKO mice. Importantly, antibody-mediated neutralization of FGF21 abolished the healthier metabolic phenotype and adipose browning in LKO mice, indicating that the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice. </p> <p><b>Conclusions</b></p> Liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD.

scholarly journals Specific inhibition of mitochondrial fatty acid oxidation by 2-bromopalmitate and its co-enzyme A and carnitine esters

1972 ◽  
Vol 129 (1) ◽  
pp. 55-65 ◽  
Author(s):  
J. F. A. Chase ◽  
P. K. Tubbs
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Liver Mitochondria ◽  
Carnitine Palmitoyltransferase ◽  
Acid Oxidation ◽  
Dependent Manner ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Succinate Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Long Chain

1. The CoA and carnitine esters of 2-bromopalmitate are extremely powerful and specific inhibitors of mitochondrial fatty acid oxidation. 2. 2-Bromopalmitoyl-CoA, added as such or formed from 2-bromopalmitate, inhibits the carnitine-dependent oxidation of palmitate or palmitoyl-CoA, but not the oxidation of palmitoylcarnitine, by intact liver mitochondria. 3. 2-Bromopalmitoylcarnitine inhibits the oxidation of palmitoylcarnitine as well as that of palmitate or palmitoyl-CoA. It has no effect on succinate oxidation, but inhibits that of pyruvate, 2-oxoglutarate or hexanoate; however, the oxidation of these substrates (but not of palmitate, palmitoyl-CoA or palmitoyl-carnitine) is restored by carnitine. 4. In damaged mitochondria, added 2-bromopalmitoyl-CoA does inhibit palmitoylcarnitine oxidation; pyruvate oxidation is unaffected by the inhibitor alone, but is impaired if palmitoylcarnitine is subsequently added. 5. The findings have been interpreted as follows. 2-Bromopalmitoyl-CoA inactivates (in a carnitine-dependent manner) a pool of carnitine palmitoyltransferase which is accessible to external acyl-CoA. This results in inhibition of palmitate or palmitoyl-CoA oxidation. A second pool of carnitine palmitoyltransferase, inaccessible to added acyl-CoA in intact mitochondria, can generate bromopalmitoyl-CoA within the matrix from external 2-bromopalmitoylcarnitine; this reaction is reversible. Such internal 2-bromopalmitoyl-CoA inactivates long-chain β-oxidation (as does added 2-bromopalmitoyl-CoA if the mitochondria are damaged) and its formation also sequesters intramitochondrial CoA. Since this CoA is shared by pyruvate and 2-oxoglutarate dehydrogenases, the oxidation of their substrates is depressed by 2-bromopalmitoylcarnitine, unless free carnitine is available to act as a ‘sink’ for long-chain acyl groups. 6. These effects are compared with those reported for other inhibitors of fatty acid oxidation.

FAT/CD36 is located on the outer mitochondrial membrane, upstream of long-chain acyl-CoA synthetase, and regulates palmitate oxidation

2011 ◽  
Vol 437 (1) ◽  
pp. 125-134 ◽  
Author(s):  
Brennan K. Smith ◽  
Swati S. Jain ◽  
Stéphanie Rimbaud ◽  
Aaron Dam ◽  
Joe Quadrilatero ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Mitochondrial Membrane ◽  
Functional Role ◽  
Muscle Fibres ◽  
Fatty Acid Transport ◽  
Outer Mitochondrial Membrane ◽  
Acid Transport ◽  
Mitochondrial Fatty Acid ◽  
Chain Acyl ◽  
Long Chain

FAT/CD36 (fatty acid translocase/Cluster of Differentiation 36), a plasma membrane fatty-acid transport protein, has been found on mitochondrial membranes; however, it remains unclear where FAT/CD36 resides on this organelle or its functional role within mitochondria. In the present study, we demonstrate, using several different approaches, that in skeletal muscle FAT/CD36 resides on the OMM (outer mitochondrial membrane). To determine the functional role of mitochondrial FAT/CD36 in this tissue, we determined oxygen consumption rates in permeabilized muscle fibres in WT (wild-type) and FAT/CD36-KO (knockout) mice using a variety of substrates. Despite comparable muscle mitochondrial content, as assessed by unaltered mtDNA (mitochondrial DNA), citrate synthase, β-hydroxyacyl-CoA dehydrogenase, cytochrome c oxidase complex IV and respiratory capacities [maximal OXPHOS (oxidative phosphorylation) respiration] in WT and KO mice, palmitate-supported respiration was 34% lower in KO animals. In contrast, palmitoyl-CoA-supported respiration was unchanged. These results indicate that FAT/CD36 is key for palmitate-supported respiration. Therefore we propose a working model of mitochondrial fatty-acid transport, in which FAT/CD36 is positioned on the OMM, upstream of long-chain acyl-CoA synthetase, thereby contributing to the regulation of mitochondrial fatty-acid transport. We further support this model by providing evidence that FAT/CD36 is not located in mitochondrial contact sites, and therefore does not directly interact with carnitine palmitoyltransferase-I as original proposed.

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