scholarly journals Mitochondrial dysfunction in fatty acid oxidation disorders: insights from human and animal studies

2016 ◽  
Vol 36 (1) ◽  
Author(s):  
Moacir Wajner ◽  
Alexandre Umpierrez Amaral
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Mitochondrial Dysfunction ◽  
Fatty Acid Oxidation ◽  
Animal Studies ◽  
Acid Oxidation ◽  
Fatty Acid Oxidation Disorders ◽  
Skeletal Myopathy ◽  
Mitochondrial Functions

Patients affected by FAOD commonly present with hepatopathy, cardiomyopathy, skeletal myopathy and encephalopathy. Human and animal evidences indicate that mitochondrial functions are disrupted by fatty acids and derivatives accumulating in these disorders, suggesting that lipotoxicity may contribute to their pathogenesis.

scholarly journals Human placenta metabolizes fatty acids: implications for fetal fatty acid oxidation disorders and maternal liver diseases

2003 ◽  
Vol 284 (6) ◽  
pp. E1098-E1105 ◽  
Author(s):  
Prem Shekhawat ◽  
Michael J. Bennett ◽  
Yoel Sadovsky ◽  
D. Michael Nelson ◽  
Dinesh Rakheja ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Human Placenta ◽  
Liver Diseases ◽  
Developmental Expression ◽  
Acid Oxidation ◽  
Fatty Acid Oxidation Disorders ◽  
Maternal Liver ◽  
Elevated Liver Enzymes

The role of fat metabolism during human pregnancy and in placental growth and function is poorly understood. Mitochondrial fatty acid oxidation disorders in an affected fetus are associated with maternal diseases of pregnancy, including preeclampsia, acute fatty liver of pregnancy, and the hemolysis, elevated liver enzymes, and low platelets syndrome called HELLP. We have investigated the developmental expression and activity of six fatty acid β-oxidation enzymes at various gestational-age human placentas. Placental specimens exhibited abundant expression of all six enzymes, as assessed by immunohistochemical and immunoblot analyses, with greater staining in syncytiotrophoblasts compared with other placental cell types. β-Oxidation enzyme activities in placental tissues were higher early in gestation and lower near term. Trophoblast cells in culture oxidized tritium-labeled palmitate and myristate in substantial amounts, indicating that the human placenta utilizes fatty acids as a significant metabolic fuel. Thus human placenta derives energy from fatty acid oxidation, providing a potential explanation for the association of fetal fatty acid oxidation disorders with maternal liver diseases in pregnancy.

scholarly journals Clinical manifestations and management of fatty acid oxidation disorders

2020 ◽  
Vol 21 (4) ◽  
pp. 479-493
Author(s):  
J. Lawrence Merritt ◽  
Erin MacLeod ◽  
Agnieszka Jurecka ◽  
Bryan Hainline
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Tricarboxylic Acid Cycle ◽  
Clinical Manifestations ◽  
Signs And Symptoms ◽  
High Energy ◽  
Acid Oxidation ◽  
Fatty Acid Oxidation Disorders ◽  
Organ Systems

Abstract Fatty acid oxidation disorders (FAOD) are a group of rare, autosomal recessive, metabolic disorders caused by variants of the genes for the enzymes and proteins involved in the transport and metabolism of fatty acids in the mitochondria. Those affected by FAOD are unable to convert fatty acids into tricarboxylic acid cycle intermediates such as acetyl-coenzyme A, resulting in decreased adenosine triphosphate and glucose for use as energy in a variety of high-energy–requiring organ systems. Signs and symptoms may manifest in infants but often also appear in adolescents or adults during times of increased metabolic demand, such as fasting, physiologic stress, and prolonged exercise. Patients with FAOD present with a highly heterogeneous clinical spectrum. The most common clinical presentations include hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, rhabdomyolysis, and skeletal myopathy, as well as peripheral neuropathy and retinopathy in some subtypes. Despite efforts to detect FAOD through newborn screening and manage patients early, symptom onset can be sudden and serious, even resulting in death. Therefore, it is critical to identify quickly and accurately the key signs and symptoms of patients with FAOD to manage metabolic decompensations and prevent serious comorbidities.

scholarly journals Lipidomic and Proteomic Alterations Induced by Even and Odd Medium-Chain Fatty Acids on Fibroblasts of Long-Chain Fatty Acid Oxidation Disorders

2021 ◽  
Vol 22 (19) ◽  
pp. 10556
Author(s):  
Khaled I. Alatibi ◽  
Stefan Tholen ◽  
Zeinab Wehbe ◽  
Judith Hagenbuchner ◽  
Daniela Karall ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Chain Fatty Acid ◽  
Acid Oxidation ◽  
Long Chain Fatty Acid ◽  
Fatty Acid Oxidation Disorders ◽  
Medium Chain ◽  
Medium Chain Fatty Acids ◽  
Long Chain

Medium-chain fatty acids (mc-FAs) are currently applied in the treatment of long-chain fatty acid oxidation disorders (lc-FAOD) characterized by impaired β-oxidation. Here, we performed lipidomic and proteomic analysis in fibroblasts from patients with very long-chain acyl-CoA dehydrogenase (VLCADD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) deficiencies after incubation with heptanoate (C7) and octanoate (C8). Defects of β-oxidation induced striking proteomic alterations, whereas the effect of treatment with mc-FAs was minor. However, mc-FAs induced a remodeling of complex lipids. Especially C7 appeared to act protectively by restoring sphingolipid biosynthesis flux and improving the observed dysregulation of protein homeostasis in LCHADD under control conditions.

scholarly journals Fatty Acid Oxidation and Its Relation with Insulin Resistance and Associated Disorders

2016 ◽  
Vol 68 (Suppl. 3) ◽  
pp. 15-20 ◽  
Author(s):  
Gary D. Lopaschuk
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Animal Studies ◽  
Glucose Oxidation ◽  
Acid Oxidation ◽  
Insulin Resistant ◽  
Novel Approach ◽  
Obesity And Diabetes

Alterations in muscle fatty acid metabolism have been implicated in mediating the severity of insulin resistance. In the insulin resistant heart fatty acids are favored as an energy source over glucose, which is thus associated with increased fatty acid oxidation, and an overall decrease in glycolysis and glucose oxidation. In addition, excessive uptake and beta-oxidation of fatty acids in obesity and diabetes can compromise cardiac function. In animal studies, mice fed a high fat diet (HFD) show cardiac insulin resistance in which the accumulation of intra-myocardial diacylglycerol has been implicated, likely involving parallel signaling pathways. A HFD also results in accumulation of fatty acid oxidation byproducts in muscle, further contributing to insulin resistance. Carnitine acetyltransferase (CrAT) has an essential role in the cardiomyocyte because of its need for large amounts of carnitine. In the cardiomyocyte, carnitine switches energy substrate preference in the heart from fatty acid oxidation to glucose oxidation. This carnitine-induced switch in fatty acid oxidation to glucose oxidation is due to the presence of cytosolic CrAT and reverse CrAT activity. Accordingly, inhibition of fatty acid oxidation, or stimulation of CrAT, may be a novel approach to treatment of insulin resistance.

scholarly journals Mitochondrial Fission Governed by Drp1 Regulates Exogenous Fatty Acid Usage and Storage in Hela Cells

Metabolites ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 322
Author(s):  
Jae-Eun Song ◽  
Tiago C. Alves ◽  
Bernardo Stutz ◽  
Matija Šestan-Peša ◽  
Nicole Kilian ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Lipid Droplets ◽  
Mitochondrial Fission ◽  
Acid Oxidation ◽  
Mitochondrial Morphology ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
And Storage

In the presence of high abundance of exogenous fatty acids, cells either store fatty acids in lipid droplets or oxidize them in mitochondria. In this study, we aimed to explore a novel and direct role of mitochondrial fission in lipid homeostasis in HeLa cells. We observed the association between mitochondrial morphology and lipid droplet accumulation in response to high exogenous fatty acids. We inhibited mitochondrial fission by silencing dynamin-related protein 1(DRP1) and observed the shift in fatty acid storage-usage balance. Inhibition of mitochondrial fission resulted in an increase in fatty acid content of lipid droplets and a decrease in mitochondrial fatty acid oxidation. Next, we overexpressed carnitine palmitoyltransferase-1 (CPT1), a key mitochondrial protein in fatty acid oxidation, to further examine the relationship between mitochondrial fatty acid usage and mitochondrial morphology. Mitochondrial fission plays a role in distributing exogenous fatty acids. CPT1A controlled the respiratory rate of mitochondrial fatty acid oxidation but did not cause a shift in the distribution of fatty acids between mitochondria and lipid droplets. Our data reveals a novel function for mitochondrial fission in balancing exogenous fatty acids between usage and storage, assigning a role for mitochondrial dynamics in control of intracellular fuel utilization and partitioning.

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