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Muscle Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Kourosh Rezania, Peter Pytel, Betty Soliven
Autosomal recessive disorder caused by impaired transport of free fatty acids into mitochondria. The abnormal gene maps to chromosome 1. Carnitine palmitoyltransferase II (CPT2) deficiency is the most common inherited cause of recurrent myoglobinuria.
Mitochondrial Dysfunction and Oxidative Stress in the Pathogenesis of Metabolic Syndrome
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Regulation of FA β-oxidation is a major physiological function of PPARα. FAs are transported into cells by membrane-bound fatty acid transport proteins (FATPs)85. FATP1 is a direct PPARα target gene, which catalyses esterification of long-chain FAs (LCFAs) and very long-chain FAs (VCFA) into acyl-CoA derivatives in a ATP-dependent manor86,87. FAT/CD36 is another plasma membrane FA transporter which is positively regulated by PPARα signalling88. In rodents and primates, FA transport across the mitochondrial membrane is regulated by Carnitine palmitoyltransferase I (CPT-I) and Carnitine palmitoyltransferase II (CPT-II), two protein enzymes localized in the outer and inner mitochondrial membrane, respectively89–91. Moreover, PPARα regulates the crucial reaction of mitochondrial β-oxidation by directly controlling expression of enzymes involved in FA β-oxidation catabolic steps, including MCAD, LCAD, and VLCAD92,93. In the liver, PPARα activation, in combination with PPARβ/δ agonist, improves hepatic steatosis, inflammation and liver fibrosis in animal model of non-alcoholic fatty liver disease (NAFLD)94. PPARs further play essential roles during placental, embryonic fetal development, and in the physiological processes of oxidative stress, inflammation, and neurodegeneration95–97.
Mitochondrial Function in Diabetes: Pathophysiology and Nutritional Therapeutics
Published in Jeffrey I. Mechanick, Elise M. Brett, Nutritional Strategies for the Diabetic & Prediabetic Patient, 2006
Insulin regulation of carnitine palmitoyltransferase I (CPT I) is a critical step in mitochondrial fatty acid-glucose crosstalk [222]. This step is modulated by fasting, high-carbohydrate diets, high-fat diets, and diabetes [220]. CPT I is an outer mitochondrial membrane enzyme that catalyzes the formation of long-chain acylcarnitines. Carnitine-acyl-carnitine translocase (CACT) transports long-chain acylcarnitines across membranes. Carnitine palmitoyltransferase II (CPT II) is an IM enzyme that reconverts long-chain acylcarnitines into their long-chain acyl CoA thioesters. These long-chain acyl CoAs are β-oxidized into acetyl CoA, which activates gluconeogenesis via pyruvate decarboxylase. Malonyl CoA mediates glucose toxicity and regulates β-cell GSIS via allosteric inhibition of CPT I [63,129,130]. Malonyl CoA fuel sensing is influenced by insulin, glucose, exercise, and AMPK activation [63,130].
Metabonomics analysis of liver in rats administered with chronic low-dose acrylamide
Published in Xenobiotica, 2020
Yanli Liu, Ruijuan Wang, Kai Zheng, Youwei Xin, Siqi Jia, Xiujuan Zhao
AA (99.8% purity) was supplied by Sigma-Aldrich (St. Louis, Missouri, USA). UPLC-grade methanol and acetonitrile were purchased from Dikma Science and Technology Co. Ltd. (Los Angeles, California, USA). UPLC-grade formic acid was obtained from Beijing Reagent Corporation (Beijing, China). Standards of sphingosine 1-phosphate (S1P) (98% purity), stearidonyl carnitine (97% purity), and cervonyl carnitine (97% purity) were purchased from Sigma-Aldrich (St. Louis, Missouri, USA). Standard of docosapentaenoic acid (DPA) (98% purity) was obtained from American Radiolabeled Chemicals Inc. (St. Louis, Missouri, USA). Standards of docosahexaenoic acid (DHA) (98% purity), and alpha-linolenic acid (ALA) (98% purity) were purchased from Cayman Chemical (Ann Arbor, Michigan, USA). Standards of tauro-b-muricholic acid (98% purity), taurodeoxycholic acid (98% purity), and linoleyl carnitine (98% purity) were purchased from Toronto Research Chemicals Inc. (Toronto, CA). The kits for total protein, superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and malondialdehyde (MDA) were all obtained from Nanjing Jiancheng Bioengineering Institute (Nanjing, China). Enzyme-linked immunosorbent assay kit for carnitine palmitoyltransferase II (CPT II) was purchased from Shanghai Jianglai Biotechnology Co., Ltd. (Shanghai, China). Deionized water was purified using a Milli-Q ultrapure water system (Millipore, Billerica, MA, USA). Leucine enkephalin was purchased from Sigma-Aldrich (St. Louis, Missouri, USA). All other chemicals and reagents were analytical-grade products.
Inherited hyperammonemias: a Contemporary view on pathogenesis and diagnosis
Published in Expert Opinion on Orphan Drugs, 2018
Evelina Maines, Giovanni Piccoli, Antonia Pascarella, Francesca Colucci, Alberto B. Burlina
The most common FAODs presenting with hyperammonemia are carnitine uptake deficiency (CUD, OMIM #212140), carnitine acylcarnitine translocase deficiency (CACTD, OMIM #212138), the neonatal and infantile forms of carnitine palmitoyltransferase II deficiency (CPT II deficiency, OMIM #608836, #600649), medium-chain acyl-CoA dehydrogenase deficiency (MCADD, OMIM #201450) and multiple acyl-CoA dehydrogenase deficiency (MADD, OMIM #231680) [80]. While there is the possibility that many patients died without being diagnosed or are symptomatic but undiagnosed, it is also very likely that many undiagnosed individuals with these disorders are asymptomatic. There is considerable evidence that many infants identified by NBS with MCADD remain asymptomatic. Early infancy treatment is not likely the reason. It is therefore probable that many, perhaps most, of the infants identified with MCADD by NBS have a mild and perhaps asymptomatic form of the disorder [81].
Current understanding and controversies on the clinical implications of fibroblast growth factor 21
Published in Critical Reviews in Clinical Laboratory Sciences, 2021
Plasma FGF21 measurement may serve as a biomarker for mitochondrial diseases, as reviewed recently [131]. In 2011, a study analyzed serum or plasma FGF21 levels in patients with or without mitochondrial disorders, diagnosed by muscle biopsy. FGF21 levels were shown to be elevated in diagnosed patients [132]. This study highlighted that the mean (standard deviation) serum FGF21 level was 820 (1151) pg/mL in adult patients and 1983 (1550) pg/mL in child patients, in comparison with 76 (58) pg/mL observed in healthy controls [132]. During the past few years, we have, however, seen different outcomes in measuring the correlation between mitochondrial diseases and serum FGF21 levels [133,134]. Carnitine palmitoyltransferase I (CPT I) and carnitine palmitoyltransferase II (CPT II) are important for mitochondrial respiratory chain functions. Liver-specific CPT II KO mice exhibited elevated serum FGF21 levels [135]. In patients diagnosed with CPT II deficiency, however, serum FGF21 levels appear to be normal [136]. In subjects with mitochondrial dysfunction in acute‐on‐chronic liver failure (ACLF), FGF21 levels were shown to be elevated, although there was no clear correlation between the severity of ACLF and FGF21 level elevation [137]. Furthermore, a study suggested that growth differentiation factor-15 (GDF-15) may be a better diagnostic biomarker for inherent mitochondrial diseases [138]. FGF21 levels in patients with mitochondrial diseases, especially in adult patients with chronic progressive external ophthalmoplegia, were also shown to be elevated [139]. It appears that as a diagnostic biomarker for mitochondrial diseases, FGF21 exhibited a low sensitivity but high specificity [139].