Type 2 Diabetes in Childhood
Emmanuel C. Opara, Sam Dagogo-Jack in Nutrition and Diabetes, 2019
In normal states, BCAAs serve an anabolic function and are involved in the synthesis of proteins. BCAA are taken into mammalian cells through a large neutral amino acid transporter (LAT1) that is involved in transport of other amino acids as well. Overload of BCAA and other amino acids due to exogenous intake or altered metabolism may lead to competition of this transporter and excessive levels of BCAAs (Figure 14.3) [13]. Accumulation of C3-acylcarnitine from metabolism of valine and isoleucine and accumulation of C5-acylcarnitine from metabolism of isoleucine and leucine suggest that altered flux through the BCAA catabolic pathway may be responsible for IR. In normal states, acylcarnitines are transported into the mitochondria, where they are metabolized into free carnitine and a long-chain acyl-CoA. Free carnitine returns to the cytosol, and the acyl-Coa undergoes fatty acid oxidation (FAO) for ATP production via the tricarboxylic acid (TCA) cycle and respiratory chain. In normal states, insulin enables cellular uptake and use of carnitine. In obese and IR states, free carnitine is lower because of increased use (from excess of substrate and higher FAO relative to TCA activity) or because of IR (from impaired cellular uptake). With lower carnitine, there is reduced ability to transport acylcarnitines into the mitochondria, and cystosolic acylcarnitines may compound the IR through impairment of insulin signaling [15].
Introduction to disorders of fatty acid oxidation
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
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 Cardiology
Stephen T. Sinatra, Mark C. Houston in Nutritional and Integrative Strategies in Cardiovascular Medicine, 2015
The principal role of carnitine is to facilitate the transport of fatty acids across the inner mitochondrial membrane to initiate β-oxidation. The inner mitochondrial membrane is normally impermeable to activated coenzyme A (CoA) esters. To affect transfer of the extracellular metabolic by-product acyl-CoA across the cellular membrane, the mitochondria deliver its acyl unit to the carnitine residing in the inner mitochondrial membrane. Carnitine (as acetyl-carnitine) then transports the metabolic fragment across the membrane and delivers it to coenzyme A residing inside the mitochondria. This process of acetyl transfer is known as carnitine shuttle, and the shuttle also works in reverse to remove excess acetyl units from the inner mitochondria for disposal. Excess acetyl units that accumulate inside the mitochondria disturb the metabolic burning of fatty acids.
Association between carnitine deficiency and the erythropoietin resistance index in patients undergoing peritoneal dialysis: a cross-sectional observational study
Published in Renal Failure, 2020
Shohei Kaneko, Keiji Hirai, Junki Morino, Saori Minato, Katsunori Yanai, Yuko Mutsuyoshi, Hiroki Ishii, Momoko Matsuyama, Taisuke Kitano, Mitsutoshi Shindo, Akinori Aomatsu, Haruhisa Miyazawa, Yuichiro Ueda, Kiyonori Ito, Susumu Ookawara, Yoshiyuki Morishita
Carnitine is an essential amino-acid derivative and plays pivotal roles in fatty-acid metabolism in skeletal muscle and cardiac muscle [1–3]. Carnitine is present in two forms in the body, acyl carnitine and free carnitine, and the sum of them is defined as total carnitine [4]. Free carnitine is converted to acylcarnitine by binding to an acyl residue. Additionally, acyl carnitine functions as a transporter of fatty acids to mitochondria and as a scavenger of excess and harmful acyl residues in cells [4]. A total of 75% of carnitine in the body is obtained by dietary intake, such as red meats, and the remaining 25% is biosynthesized by the kidney and liver [5,6]. In healthy individuals, most of the free carnitine is re-reabsorbed in the kidney, and acyl carnitine is preferentially excreted into urine. Carnitine homeostasis in the body is maintained by this mechanism.
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].
Predictive value of metabolomic biomarkers for cardiovascular disease risk: a systematic review and meta-analysis
Published in Biomarkers, 2020
Peter McGranaghan, Anshul Saxena, Muni Rubens, Jasmin Radenkovic, Doris Bach, Leonhard Schleußner, Burkert Pieske, Frank Edelmann, Tobias Daniel Trippel
Lipids and their metabolic pathways are the primary focus in CVD pathophysiology and thus represent a valuable target for metabolomic profiling based risk assessment amenable to clinical use (Di Angelantonio et al. 2009, Wende and Abel 2010, Goldberg et al. 2012). Altered lipid metabolism and dyslipidaemia are known to be associated with altered fatty acid metabolism and mitochondrial dysfunction which are primary drivers of the pathological changes in CVD (Lopaschuk 2010). In this meta-analysis, acylcarnitines were significantly associated with a higher risk of fatal CVD outcomes, which are a group of metabolites responsible for regulating energy and fatty acid metabolism previously found to be independently associated with clinical outcomes (Ahmad 2016). Carnitine plays an essential role in the energy homeostasis of the myocardium via the transfer of long‐chain fatty acids across the inner mitochondrial membrane. Altered acylcarnitine levels are representative of dysregulated carnitine metabolism which can lead to the accumulation of intracellular long-chain fatty acid metabolites and increased circulating free fatty acids. This perturbed homeostasis of mitochondrial and fatty acid metabolism can contribute to worsening CHF, arrhythmias, insulin resistance, adverse remodelling and decreased energy production.
Related Knowledge Centers
- Fatty Acid
- In Vivo
- Stereoisomerism
- Vegetarianism
- Metabolism
- Cardiac Muscle
- Skeletal Muscle
- Quaternary Ammonium Cation
- Mitochondrion
- Redox