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Introduction to disorders of fatty acid oxidation
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The normal response to fasting and the oxidation of fat begins with lipolysis, which releases free-fatty acids. In patients with disorders of fatty acid oxidation, concentrations of free-fatty acids are usually higher than those of 3-hydroxybutyrate in blood at times of illness and metabolic stress. Thus, assessment of the concentrations of free fatty acids and 3-hydroxybutyrate in the blood is essential to the diagnosis of hypoketosis. Because fatty acids that accumulate in the presence of defective oxidation undergo ω-oxidation to dicarboxylic acids, a disproportionate ratio of dicarboxylic acids to 3-hydroxybutyrate in the organic acid analysis of the urine also indicates disordered fatty acid oxidation. Transport of long-chain fatty acids into the mitochondria, where ß-oxidation takes place, requires carnitine, and the entry of carnitine into cells such as muscle requires a specific transporter, which may be deficient in an inborn error of metabolism [6] (Chapter 35). Esterification of carnitine with fatty acyl CoA ester is catalyzed by acyltransferases, such as carnitine palmitoyl transferase (CPT) I (Chapter 37). The transport of the acylcarnitine across the mitochondrial membrane is catalyzed by carnitine translocase (Chapter 36); and then hydrolysis, releasing carnitine and the fatty acylCoA, is catalyzed by a second acyltransferase, CPT II (Chapters 37 and 38). Inborn errors are known for each of these three enzymatic steps. In ß-oxidation, the fatty acid is successively shortened by two carbons, releasing acetylCoA.
Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
Routine investigations, especially when unwell, usually reveal a metabolic ketoacidosis. Urine organic acids show grossly elevated methylmalonic acid or propionic acid. An acylcarnitine profile reveals an elevated propionylcarnitine (C3). Vitamin B12 and total homocysteine level should be measured in methylmalonic acidaemia (MMA) to rule out the associated disorders of cobalamin metabolism. Diagnosis can be confirmed by enzymology and/or molecular genetics.
Alterations in Myocardial Energy Metabolism in Streptozotocin Diabetes
Published in John H. McNeill, Experimental Models of Diabetes, 2018
William C. Stanley, Gary D. Lopaschuk, Krista M. Kivilo
Esterified fatty acids are transferred across the mitochondrial membrane into the mitochondrial matrix by three carnitine dependent enzymes. The first one in the sequence, carnitine-palmitoyl transferase I (CPT I), catalyzes the formation of long-chain acylcarnitine from long-chain acyl CoA in the compartment between the inner and outer mitochondrial membrane (see Figure 2.4). The second enzyme, carnitine: acylcarnitine translocase, transports long-chain acylcarnitine across the inner mitochondrial membrane, whereas the last one in the sequence, carnitine palmitoyl transferase II (CPT II), regenerates long-chain acyl CoA in the mitochondrial matrix. Of the three enzymes involved in the transmitochondrial membrane transport, CPT I serves as the key regulatory enzyme. CPT I activity is inhibited by malonyl CoA, which is formed from carboxylation of acetyl CoA by acetyl CoA carboxylase (ACC) (see Figure 2.4). In STZ diabetic rat hearts, the authors have demonstrated that control of malonyl CoA production can be markedly repressed in diabetes. ACC expression and mRNA levels are not altered in STZ diabetic rat or swine hearts;22,23,37 however, a significant depression of ACC activity has been observed.54 This decrease occurs even in the presence of saturating concentrations of acetyl CoA. The above observation contrasts with data obtained from hepatic and adipose tissue measurements, in which a dramatic decrease in ACC expression occurs in STZ diabetes. ACC regulation is attributed to the cAMP-activated protein kinase and the 5′-AMP-activated protein kinase (AMPK). Phosphorylation of ACC inhibits its activity. In diabetes this regulation is induced by the increased activity in AMPK that, in turn, is activated by phosphorylation via a specific AMPK. ACC phosphorylation and inhibition lead to lower levels of malonyl CoA and removes the inhibition upon CPT I. These changes result in the enhancement of mitochondrial fatty acid uptake and oxidation in the diabetic heart. Such an increase in fatty acid oxidation is paralleled by a decrease in carbohydrate oxidation.
Serum metabolic alterations in peritoneal dialysis patients with excessive daytime sleepiness
Published in Renal Failure, 2023
Wei Chen, Ying Xu, Zheng-Hao Li, Ya-Chen Si, Hai-Yan Wang, Xiao-Lu Bian, Lu Li, Zhi-Yong Guo, Xue-Li Lai
Carnitine was another amino acid that was significantly different between the EDS and non-EDS groups. Previous studies have shown that mice with systemic carnitine deficiency exhibit a higher frequency of fragmented wakefulness and rapid eye movement sleep and reduced locomotor activity, indicating that carnitine is essential for normal sleep regulation [29]. In clinical research, acylcarnitine levels in blood samples were significantly lower in narcolepsy patients than in controls. In addition, the expression of carnitine palmitoyltransferase 1B was higher in narcolepsy patients, suggesting that fatty acid β-oxidation is altered in narcolepsy patients [30]. Then, a randomized, double-blind, crossover and placebo-controlled trial administering carnitine to patients with narcolepsy was performed. The results showed that carnitine is an effective and well-tolerated treatment for daytime sleepiness in narcolepsy patients [31]. Therefore, we hypothesize that carnitine treatment may ameliorate EDS in PD patients by promoting fatty acid oxidation.
Targeting cellular energy metabolism- mediated ferroptosis by small molecule compounds for colorectal cancer therapy
Published in Journal of Drug Targeting, 2022
Gang Wang, Jun-Jie Wang, Xiao-Na Xu, Feng Shi, Xing-Li Fu
Fatty acid metabolic enzymes are related to the prognosis and progression of several cancers, including colorectal cancer [40,41]. Notably, acyl CoA synthetase (ACSL) expression and clinical outcomes indicate that ACSL1, which is used more for triglyceride synthesis [42], is upregulation in CRC [43]. Acylcarnitines are generated through the transfer of carnitine for CoA on acyl-CoA derivatives of long-chain FA by carnitine palmitoyltransferase (CPT), to transport them through the mitochondrial membrane [44]. Thus, elevated acylcarnitine levels can be due to increased CPT activity resulting from an increase in the cytoplasmic acyl-CoA substrate levels, such as the ACSL1 products. Regarding glycolytic perturbations, increased phosphoenolpyruvate (PEP) levels and normal pyruvate could be a reflection of less of a demand of TCA feeding from pyruvate (from carbohydrates) explaining a lower basal oxygen consumption rate (OCR), since a more energetic status is achieved through other alternative supplies, such as FAO, that could be fed by ACSL1 overexpression [45]. For instance, the FAO inhibitor etomoxir is insufficient for reversing the EMT phenotype of ACSL/SCD cells that, conversely, can be achieved upon a more drastic energetic restriction caused by the reactivation of AMP-activated protein kinase (AMPK) signalling upon metformin treatment [46].
Exploring the contribution of mitochondrial dynamics to multiple acyl-CoA dehydrogenase deficiency-related phenotype
Published in Archives of Physiology and Biochemistry, 2021
Sofia R. Brandão, Rita Ferreira, Hugo Rocha
In overall, there are at least twenty-five enzymes and specific transport proteins involved in FAO and defects in many of them are associated with human diseases, generally designated as FAOD (Vockley and Whiteman 2002, Kompare and Rizzo 2008, Moczulski et al.2009, Rocha et al.2014). These disorders are generally inherited in an autosomal recessive pattern and are individually rare, although they are collectively common (Kompare and Rizzo 2008, Sahai and Marsden 2009). Most FAOD are identified by the acylcarnitine profile analyzed by flow injection electrospray ionization (ESI) tandem mass spectrometry (MS/MS) (Lindner et al.2010, Wilcken 2010). In fact, the acylcarnitine profile data obtained from NBS programs is crucial for the diagnosis of FAOD (Rocha et al.2014).