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      A general introduction to the biochemistry of mitochondrial fatty acid β-oxidation

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      Journal of Inherited Metabolic Disease
      Springer Netherlands

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          Abstract

          Over the years, the mitochondrial fatty acid β-oxidation (FAO) pathway has been characterised at the biochemical level as well as the molecular biological level. FAO plays a pivotal role in energy homoeostasis, but it competes with glucose as the primary oxidative substrate. The mechanisms behind this so-called glucose–fatty acid cycle operate at the hormonal, transcriptional and biochemical levels. Inherited defects for most of the FAO enzymes have been identified and characterised and are currently included in neonatal screening programmes. Symptoms range from hypoketotic hypoglycaemia to skeletal and cardiac myopathies. The pathophysiology of these diseases is still not completely understood, hampering optimal treatment. Studies of patients and mouse models will contribute to our understanding of the pathogenesis and will ultimately lead to better treatment.

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          Most cited references66

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          Peroxisome proliferator-activated receptor alpha target genes.

          Peroxisome proliferator-activated receptors (PPARs) are nuclear proteins that belong to the superfamily of nuclear hormone receptors. They mediate the effects of small lipophilic compounds such as long-chain fatty acids and their derivatives on transcription of genes commonly called PPAR target genes. Here we review the involvement of PPARalpha in peroxisomal and mitochondrial fatty acid oxidation, microsomal fatty acid hydroxylation, lipoprotein, bile and amino acid metabolism, glucose homeostasis, biotransformation, inflammation control, hepato-carcinogenesis and other pathways, through a detailed analysis of the different known or putative PPARalpha target genes.
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            The Randle cycle revisited: a new head for an old hat.

            In 1963, Lancet published a paper by Randle et al. that proposed a "glucose-fatty acid cycle" to describe fuel flux between and fuel selection by tissues. The original biochemical mechanism explained the inhibition of glucose oxidation by fatty acids. Since then, the principle has been confirmed by many investigators. At the same time, many new mechanisms controlling the utilization of glucose and fatty acids have been discovered. Here, we review the known short- and long-term mechanisms involved in the control of glucose and fatty acid utilization at the cytoplasmic and mitochondrial level in mammalian muscle and liver under normal and pathophysiological conditions. They include allosteric control, reversible phosphorylation, and the expression of key enzymes. However, the complexity is formidable. We suggest that not all chapters of the Randle cycle have been written.
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              Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects.

              Carnitine palmitoyltransferase (CPT) deficiencies are common disorders of mitochondrial fatty acid oxidation. The CPT system is made up of two separate proteins located in the outer (CPT1) and inner (CPT2) mitochondrial membranes. While CPT2 is an ubiquitous protein, three tissue-specific CPT1 isoforms--the so-called "liver" (CPT1-A), "muscle" (CPT1B) and (CPT1-C) CPT1s--have been shown to exist. Amino acid and cDNA nucleotide sequences have been identified for all of these proteins. CPT1-A deficiency presents as recurrent attacks of fasting hypoketotic hypoglycemia. Twenty four CPT1A mutations have been reported to date. CPT1-B and -C deficiencies have not been hitherto identified. CPT2 deficiency has several clinical presentations. The "benign" adult form (more than 200 families reported) is characterized by episodes of rhabdomyolysis triggered by prolonged exercise. The prevalent S113L mutation is found in about 50% of mutant alleles. The infantile-type CPT2 presents as severe attacks of hypoketotic hypoglycemia, occasionally associated with cardiac damage commonly responsible for sudden death before 1 year of age. In addition to these symptoms, features of brain and kidney dysorganogenesis are frequently seen in the neonatal-onset CPT2 deficiency, almost always lethal during the first month of life. Around 40 CPT2 mutations (private missense or truncating mutations) have hitherto been detected. Treatment is based upon avoidance of fasting and/or exercise, a low fat diet enriched with medium chain triglycerides and carnitine. Prenatal diagnosis may be offered for pregnancies at a 1/4 risk of infantile/severe-type CPT2 deficiency.
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                Author and article information

                Contributors
                +31-20-5665958 , +31-20-6962596 , s.m.houten@amc.uva.nl
                Journal
                J Inherit Metab Dis
                Journal of Inherited Metabolic Disease
                Springer Netherlands (Dordrecht )
                0141-8955
                1573-2665
                2 March 2010
                2 March 2010
                October 2010
                : 33
                : 5
                : 469-477
                Affiliations
                Laboratory Genetic Metabolic Diseases, Departments of Clinical Chemistry and Pediatrics, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
                Author notes

                Communicated by: Ertan Mayatepek

                Article
                9061
                10.1007/s10545-010-9061-2
                2950079
                20195903
                020d8d5e-535c-4c4d-8d8d-1c44a045775e
                © The Author(s) 2010
                History
                : 14 October 2009
                : 14 October 2009
                : 28 January 2010
                Categories
                Fatty Acid Oxidation
                Custom metadata
                © SSIEM and Springer 2010

                Internal medicine
                Internal medicine

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