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Metabolic Cardiology
Published in Stephen T. Sinatra, Mark C. Houston, Nutritional and Integrative Strategies in Cardiovascular Medicine, 2022
To summarize, without carnitine, fats which are a high-energy fuel for the heart cannot be converted to ATP. The heart uses free-fatty acids as its main energy source, and the only way for long-chain fatty acids to get to the inner mitochondrial membrane where energy is produced is via the carnitine shuttle. Thus, the addition of L-carnitine is a particularly important contribution in the synergy of metabolic cardiology.
Inborn Errors of Metabolism
Published in Praveen S. Goday, Cassandra L. S. Walia, Pediatric Nutrition for Dietitians, 2022
Surekha Pendyal, Areeg Hassan El-Gharbawy
FAO provides as much as 80% of energy for heart and liver function. In the liver, the oxidation of fatty acids fuels the synthesis of ketone bodies which are utilized as an alternative energy source by extrahepatic organs, particularly the brain. Glucose is the preferred energy source in cells and glucose derived from glycogen is used during short-term fasting. During periods of prolonged fasting, febrile illness, or increased muscular activity, fatty acids are mobilized to meet the increased energy demands. The physiologically available fatty acids are mostly the C16 and C18 (long-chain) fatty acids and their oxidation requires entry into the mitochondrial matrix using enzymes of the carnitine shuttle (Figure 23.3, steps 1–3). Once inside the mitochondria, β-oxidation of the fatty acids occurs in a repeating cycle using the four enzyme complexes (Figure 23.3, steps 4–7), each “spiral” of the cycle releasing one molecule of acetyl-CoA and leaving a fatty acyl CoA two carbons shorter for recycling through further β-oxidation. Acetyl-CoA can then enter the citric acid (CA) cycle and/or serve as the precursor for ketone production. The reducing equivalents reduced nicotinamide adenine dinucleotide (NADH) and dihydroflavine adenine dinucleotide (FADH2) produced from β-oxidation and the CA cycle enter the electron transport chain for adenosine triphosphate (ATP) production.
Carnitine-acylcarnitine translocase deficiency
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
Mitochondrial oxidation of long-chain fatty acids provides an important source of energy for the heart, as well as for skeletal muscle during prolonged aerobic work and for hepatic ketogenesis during long-term fasting. The carnitine shuttle is responsible for transferring long-chain fatty acids across the barrier of the inner mitochondrial membrane to gain access to the enzymes of β-oxidation. The shuttle consists of three enzymes (carnitine palmitoyltransferase [CPT] 1, carnitine-acylcarnitine translocase [CACT], CPT 2) and a small, soluble molecule (carnitine) to transport fatty acids as their long-chain fatty acylcarnitine esters. Carnitine is provided in the diet (animal protein) and also synthesized at low rates from trimethyllysine residues generated during protein catabolism. Carnitine turnover rates (300–500 μmol/day) represent <1 percent of body stores; 98 percent of carnitine stores are intracellular (total carnitine levels are 40–50 μM in plasma versus 2–3 mM in tissue). Carnitine is removed by urinary excretion after reabsorption of 98 percent of the filtered load; the renal carnitine threshold determines plasma concentrations and total body carnitine stores [5].
Exploring the internal exposome of seminal plasma with semen quality and live birth: A Pilot Study
Published in Systems Biology in Reproductive Medicine, 2023
Emily Houle, YuanYuan Li, Madison Schroder, Susan L McRitchie, Tayyab Rahil, Cynthia K Sites, Susan Jenkins Sumner, J. Richard Pilsner
For pathway analysis, we first used Metabanalyte 5.0 to identify the overall perturbations between LSQ and NSQ using all the normalized signals after filtering. We found that six pathways involving fatty acid biosynthesis and metabolism, vitamin A metabolism, and histidine metabolism were associated with the differentiation of LSQ and NSQ (Figure 1). We verified the empirical findings from the Metaboanalyt analysis by also matching signals to the IHPSL and PD. As shown in Figure 2, in the carnitine shuttle pathway, all the identified long-chain acylcarnitine (C14–C18) and short-chain acylcarnitine (C3–C5) were elevated in the LSQ compared to NSQ, while the medium-chain acylcarnitine (e.g., methylglutaryl carnitine), free carnitine, and deoxy carnitine were decreased. As to the vitamin A metabolism (Figure 3), retinol, retinoic acid, retinal, 3,4-didehydroretinoate, 18-hydroxyretioic acid, and 4-hydroxyretinoic acid were verified by the MS and MS/MS spectra information. We did not observe a significant difference in the level of retinol between the LSQ and NSQ, although most of the other vitamin A-related metabolites, including retinoic acids, hydroxy retinoic acids, and didehydroretinoates were lower in the LSQ than the NSQ.
Logistic role of carnitine shuttle system on radiation-induced L-carnitine and acylcarnitines alteration
Published in International Journal of Radiation Biology, 2022
CACT is located to the inner mitochondrial membrane as a carrier that transports acylcarnitines across the membrane in exchange for free L-carnitine that exits from the mitochondrial matrix (Figure 2). It can also transport the carnitine shuttle system intermediates acylcarnitines out of the mitochondria (Bennett 2007). The enzyme has high activity in most cell types, and the activity obviously exceeds of β-oxidation flux requirement greatly. Thus, CACT is not usually thought to play a role in regulating the β-oxidation flux. However, one study found that acetylation of CACT decreased the transport activity, which indicated CACT may be a possible regulatory site of β-oxidation pathway (Eaton 2002). The acetylation level plays an additional role in the control of CACT function and is affected by acetyl-CoA level and the activity of sirtuin-3. This NAD+‐dependent protein deacetylase is a member of the silent information regulator 2 family. This mechanism represents a control of the influx of fatty acyl groups into mitochondria in response to intramitochondrial acetyl-CoA level. The role of CACT on alteration of carnitine profile can be acquainted in some literature. For example, the level of palmitoylcarnitine was elevated in the CACT deficiency patients (Yamada and Taketani 2019; Houten et al. 2020).
The role of metabolomic markers for patients with infectious diseases: implications for risk stratification and therapeutic modulation
Published in Expert Review of Anti-infective Therapy, 2018
Seline Zurfluh, Thomas Baumgartner, Marc A. Meier, Manuel Ottiger, Alaadin Voegeli, Luca Bernasconi, Peter Neyer, Beat Mueller, Philipp Schuetz
Outcome prediction in sepsis and patients with CAP is challenging, but may help to direct care in the acute setting [28,29]. Several studies have investigated metabolomic markers to improve risk stratification in patients with sepsis and infections [21,22,24,30–32]. For example, in patients with severe septic shock, early changes in plasma levels of lipid species and kynurenine (KYN) are associated with higher mortality [30]. Also alterations in fatty acid metabolism appear to be a prominent phenotypical characteristic to differentiate sepsis survivors from nonsurvivors. Due to elevated acyl-carnitine plasma levels in nonsurvivors, the metabolic defect in fatty acid β-oxidation seems to be located at the level of the carnitine shuttle [32]. Rogers et al. formed a metabolomic network of seven metabolites (gamma-glutamylphenylalanine, gamma-glutamyltyrosine, 1-arachidonylGPC(20:4), taurochenodexycholate, 3-(4-hydroxyphenyl) lactate, sucrose and kynurenine) associated with ICU mortality, which reached an AUC of 0.91 for prediction of 28-day mortality [31]. In the study of Mickiewicz et al. including septic-shock patients, metabolomics performed better compared to clinical risk scores including APACHE or SOFA scores [24]. Putrescine (a diamine), lysoPCaC18:0 and SM C16:1 are able to predict unfavorable outcome in sepsis [21].