RESUMEN
Compared with other species, freshwater fish are more capable of synthesizing DHA via same biosynthetic pathways. Freshwater fish have a "Sprecher" pathway to biosynthesize DHA in a peroxisome-dependent manner. Enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase (Ehhadh) is involved in the hydration and dehydrogenation reactions of fatty acid ß-oxidation in peroxisomes. However, the role of Ehhadh in the synthesis of DHA in freshwater fish remains largely unclear. In this study, the knockout of Ehhadh significantly inhibited DHA synthesis in zebrafish. Liver transcriptome analysis showed that Ehhadh deletion significantly inhibited SREBF and PPAR signaling pathways and decreased the expression of PUFA synthesis-related genes. Our results from the analysis of transgenic zebrafish (Tg:Ehhadh) showed that Ehhadh overexpression significantly increased the DHA content in the liver and significantly upregulated the expression of genes related to PUFA synthesis. In addition, the DHA content in the liver of Tg:Ehhadh fed with linseed oil was significantly higher than that of wildtype, but the expression of PUFA synthesis-related genes fads2 and elovl2 were significantly lower, indicating that Ehhadh had a direct effect on DHA synthesis. In conclusion, our results showed that Ehhadh was essential for DHA synthesis in the "Sprecher" pathway, and Ehhadh overexpression could promote DHA synthesis. This study provides insight into the role of Ehhadh in freshwater fish.
Asunto(s)
Enoil-CoA Hidratasa , Pez Cebra , Animales , Enzima Bifuncional Peroxisomal/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismo , Enoil-CoA Hidratasa/genética , Enoil-CoA Hidratasa/metabolismo , Enoil-CoA Hidratasa/farmacología , Peroxisomas/metabolismo , Hígado/metabolismo , 3-Hidroxiacil-CoA Deshidrogenasas/genética , 3-Hidroxiacil-CoA Deshidrogenasas/metabolismo , 3-Hidroxiacil-CoA Deshidrogenasas/farmacología , Acetiltransferasas/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Amyloid-ß (Aß) peptide-binding alcohol dehydrogenase (ABAD), an enzyme present in neuronal mitochondria, exacerbates Aß-induced cell stress. The interaction of ABAD with Aß exacerbates Aß-induced mitochondrial and neuronal dysfunction. Here, we show that inhibition of the ABAD-Aß interaction, using a decoy peptide (DP) in vitro and in vivo, protects against aberrant mitochondrial and neuronal function and improves spatial learning/memory. Intraperitoneal administration of ABAD-DP [fused to the transduction of human immunodeficiency virus 1-transactivator (Tat) protein and linked to the mitochondrial targeting sequence (Mito) (TAT-mito-DP) to transgenic APP mice (Tg mAPP)] blocked formation of ABAD-Aß complex in mitochondria, increased oxygen consumption and enzyme activity associated with the mitochondrial respiratory chain, attenuated mitochondrial oxidative stress, and improved spatial memory. Similar protective effects were observed in Tg mAPP mice overexpressing neuronal ABAD decoy peptide (Tg mAPP/mito-ABAD). Notably, inhibition of the ABAD-Aß interaction significantly reduced mitochondrial Aß accumulation. In parallel, the activity of mitochondrial Aß-degrading enzyme PreP (presequence peptidase) was enhanced in Tg mAPP mitochondria expressing the ABAD decoy peptide. These data indicate that segregating ABAD from Aß protects mitochondria/neurons from Aß toxicity; thus, ABAD-Aß interaction is an important mechanism underlying Aß-mediated mitochondrial and neuronal perturbation. Inhibitors of ABAD-Aß interaction may hold promise as targets for the prevention and treatment of Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Encéfalo/ultraestructura , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , 3-Hidroxiacil-CoA Deshidrogenasas/antagonistas & inhibidores , 3-Hidroxiacil-CoA Deshidrogenasas/farmacología , 3-Hidroxiacil-CoA Deshidrogenasas/uso terapéutico , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/farmacología , Precursor de Proteína beta-Amiloide/genética , Animales , Sitios de Unión/genética , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Complejo III de Transporte de Electrones/metabolismo , Complejo IV de Transporte de Electrones/metabolismo , Ensayo de Inmunoadsorción Enzimática , Proteínas Ligadas a GPI/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Humanos , Inmunoprecipitación/métodos , Memoria/efectos de los fármacos , Memoria/fisiología , Ratones , Ratones Transgénicos , Mitocondrias/genética , Mutación/genética , Especies Reactivas de Oxígeno/metabolismo , Percepción Espacial/efectos de los fármacos , Percepción Espacial/fisiologíaRESUMEN
Introducción. La deficiencia de 3-hidroxiacil-CoA deshidrogenasa de cadena larga (LCHADD) es una enfermedad metabólica muy poco frecuente, de transmisión autosómica recesiva con expresión variable, que incluye la hipoglucemia grave, cardiomiopatía y posible muerte súbita infantil, fallo hepático progresivo, síndrome de Reye-like, déficit neurosensoriales, debilidad muscular y rabdomiólisis. Caso clínico. Niño de 3 años que llegó al servicio de urgencias con un cuadro de vómitos, disminución del nivel de conciencia e hipotonía, en el contexto de una infección respiratoria sin gravedad. El estudio analítico reveló hipoglucemia no cetósica y citólisis hepática, lo cual motivó la realización de un estudio metabólico. Se constató una disminución de la relación lactato/piruvato, hipocarnitinemia y aciduria dicarboxílica, y el perfil de los ácidos orgánicos urinarios resultó compatible con el déficit de β-oxidación, más específicamente LCHADD. El estudió genético mostró la mutación G1528C, en el gen HADHA, en homocigosis en la sangre del niño y en heterocigosis en los dos progenitores, lo cual confirmó el diagnóstico. Conclusiones. El diagnóstico de déficit de b-oxidación se debe plantear en presencia de vómitos asociados a postración desproporcionada o letargia, especialmente si se confirma hipoglucemia hipocetósica o historia familiar de muerte súbita. Es importante la sensibilización y alerta sobre la existencia de estas patologías, especialmente en lo que se refiere a la importancia del registro de la glucemia y cuerpos cetónicos urinarios en la evaluación de las situaciones de riesgo (AU)
Introduction. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a rare disease, inherited as autosomal- recessive trait, with variable clinical presentation including severe hypoglycaemia, cardiomyopathy, sudden infant death, progressive liver failure, Reye like syndrome, neuromyopathy, muscle weakness and rhabdomyolysis. Case report. We report a 3 years old male patient admitted to our emergency department with vomiting, hypotonia and prostration, after a common respiratory infection. The presence of hypoketotic hypoglycaemia and elevated liver enzymes in the admission motivated a metabolic study. We found an abnormal low lactate/pyruvate ratio, decreased serum carnitine and dicarboxylic aciduria leading to the diagnosis of a fatty acid oxidation disorder (LCHADD). The molecular study of HADHA gene revealed homozygosity for the G1528C mutation in the patient DNA, and heterozygosity in both parents. Conclusions. The diagnosis of a fatty acid oxidation disorder must be considered in the presence of vomiting associated with excessive prostration specially if there is hypoketotic hypoglycaemia or familiar sudden infant death history. Physicians should be aware about these conditions and for the importance of measuring both glycaemia and ketone bodies during the evaluation of high risk situations (AU)