RESUMO
Fructose is a major component of dietary sugar and its overconsumption exacerbates key pathological features of metabolic syndrome. The central fructose-metabolising enzyme is ketohexokinase (KHK), which exists in two isoforms: KHK-A and KHK-C, generated through mutually exclusive alternative splicing of KHK pre-mRNAs. KHK-C displays superior affinity for fructose compared with KHK-A and is produced primarily in the liver, thus restricting fructose metabolism almost exclusively to this organ. Here we show that myocardial hypoxia actuates fructose metabolism in human and mouse models of pathological cardiac hypertrophy through hypoxia-inducible factor 1α (HIF1α) activation of SF3B1 and SF3B1-mediated splice switching of KHK-A to KHK-C. Heart-specific depletion of SF3B1 or genetic ablation of Khk, but not Khk-A alone, in mice, suppresses pathological stress-induced fructose metabolism, growth and contractile dysfunction, thus defining signalling components and molecular underpinnings of a fructose metabolism regulatory system crucial for pathological growth.
Assuntos
Cardiomiopatia Hipertrófica/metabolismo , Frutoquinases/metabolismo , Frutose/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fosfoproteínas/metabolismo , Ribonucleoproteína Nuclear Pequena U2/metabolismo , Processamento Alternativo , Animais , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Cardiomiopatia Hipertrófica/fisiopatologia , Modelos Animais de Doenças , Frutoquinases/deficiência , Frutoquinases/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Isoenzimas/deficiência , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Síndrome Metabólica/metabolismo , Camundongos , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Fatores de Processamento de RNA , Ribonucleoproteína Nuclear Pequena U2/deficiência , Ribonucleoproteína Nuclear Pequena U2/genéticaRESUMO
Sideroblastic anemia is characterized by anemia with the emergence of ring sideroblasts in the bone marrow. There are two forms of sideroblastic anemia, i.e., congenital sideroblastic anemia (CSA) and acquired sideroblastic anemia. In order to clarify the pathophysiology of sideroblastic anemia, a nationwide survey consisting of clinical and molecular genetic analysis was performed in Japan. As of January 31, 2012, data of 137 cases of sideroblastic anemia, including 72 cases of myelodysplastic syndrome (MDS)-refractory cytopenia with multilineage dysplasia (RCMD), 47 cases of MDS-refractory anemia with ring sideroblasts (RARS), and 18 cases of CSA, have been collected. Hemoglobin and MCV level in CSA are significantly lower than those of MDS, whereas serum iron level in CSA is significantly higher than those of MDS. Of 14 CSA for which DNA was available for genetic analysis, 10 cases were diagnosed as X-linked sideroblastic anemia due to ALAS2 gene mutation. The mutation of SF3B1 gene, which was frequently mutated in MDS-RS, was not detected in CSA patients. Together with the difference of clinical data, it is suggested that genetic background, which is responsible for the development of CSA, is different from that of MDS-RS.
