Hepatology. 2011 Dec;54(6):1975-86


Ainara Cano, Xabier Buqué, Maite Martínez-Uña, Igor Aurrekoetxea, Ariane Menor, Juan Luis García-Rodríguez2, Shelly Lu, José María Mato, Begoña Ochoa y Patricia Aspichueta


Very low-density lipoprotein (VLDL) secretion provides a mechanism to export triglycerides (TG) from the liver to peripheral tissues, maintaining lipid homeostasis. In nonalcoholic fatty liver disease (NAFLD), VLDL secretion disturbances are unclear. Methionine adenosyltransferase (MAT) is responsible for S-adenosylmethionine (SAMe) synthesis and MAT I and III are the products of the MAT1A gene. Deficient MAT I and III activities and SAMe content in the liver have been associated with NAFLD, but whether MAT1A is required for normal VLDL assembly remains unknown. We investigated the role of MAT1A on VLDL assembly in two metabolic contexts: in 3-month-old MAT1A-knockout mice (3-KO), with no signs of liver injury, and in 8-month-old MAT1A-knockout mice (8-KO), harboring nonalcoholic steatohepatitis. In 3-KO mouse liver, there is a potent effect of MAT1A deletion on lipid handling, decreasing mobilization of TG stores, TG secretion in VLDL and phosphatidylcholine synthesis via phosphatidylethanolamine N-methyltransferase. MAT1A deletion also increased VLDL- apolipoprotein B secretion, leading to small, lipid-poor VLDL particles. Administration of SAMe to 3-KO mice for 7 days recovered crucial altered processes in VLDL assembly and features of the secreted lipoproteins. The unfolded protein response was activated in 8-KO mouse liver, in which TG accumulated and the phosphatidylcholine-to-phosphatidylethanolamine ratio was reduced in the endoplasmic reticulum, whereas secretion of TG and apolipoprotein B in VLDL was increased and the VLDL physical characteristics resembled that in 3-KO mice. MAT1A deletion also altered plasma lipid homeostasis, with an increase in lipid transport in low-density lipoprotein subclasses and decrease in high-density lipoprotein subclasses. Conclusion: MAT1A is required for normal VLDL assembly and plasma lipid homeostasis in mice. Impaired VLDL synthesis, mainly due to SAMe deficiency, contributes to NAFLD development in MAT1A-KO mice. (HEPATOLOGY 2011). Copyright © 2011 American Association for the Study of Liver Diseases.


Se han estudiado los mecanismos moleculares responsables de la secreción de lípidos por el hígado en ratones knock-out que presentan diferentes estadios de la enfermedad de hígado graso no alcohólica (NAFLD). Estos animales carecen del gen Metionina adenosiltransferasa 1A (MAT1A), que se expresa en el hígado y cataliza la síntesis de S-adenosilmetionina (SAMe), principal donador biológico de metilos. El principal hallazgo descrito es que SAMe es imprescindible para el correcto ensamblaje y secreción de lipoproteínas de baja densidad (VLDL), complejos esenciales para el mantenimiento de la homeostasis lipídica del hígado y del organismo en conjunto. Así, la deficiencia de SAMe en los ratones MAT1A-KO favorece el desarrollo de NAFLD.

Foto grupo enero

Ainara Cano realizó una tesis doctoral europea en la Facultad de Medicina de la Universidad del País Vasco (UPV/EHU), titulada “Papel del gen MAT1A en la homeostasis lipídica y orgánica de los lípidos” (2005-2009). El presente artículo es resultado de la colaboración de su grupo, investigadores del CIC bioGUNE (Bizkaia) y la Universidad de Southern California (Keck School of Medicine, USA). Conocer los mecanismos fisiopatológicos que acompañan a la enfermedad de hígado graso no alcohólica (NAFLD) es su principal desafío.
Actualmente, Ainara es investigadora en la empresa biotecnológica One Way Liver (OWL). La compañía combina servicios e I+D, siendo su objetivo encontrar marcadores no invasivos de enfermedades, especialmente NAFLD, por medio del análisis UPLC-MS de metabolitos presentes en material biológico, como suero, tejido y células.

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