Referencia

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

Autores

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

Resumen

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.

Descripción

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

REFERENCIA DEL GRUPO INVESTIGADOR
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 http://lipids-liver.net/, 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 http://owlgenomics.com/ 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.

Más artículos en la revista SEBBM.

Did you publish an interesting article recently?

Send it through our application form and we will contact you. Age limit: 32.

The selected articles will participate at the Award to the best article of young people of the SEBBM which will be given during SEBBM conference, that will take place at Spain (free registration, travel and accommodation).

More articles of the month

Functional optimization of broadly neutralizing HIV-1 antibody 10E8 by promoting membrane interactions

01-03-2018

El anticuerpo 10E8 representa uno de los anticuerpos anti-VIH con mayor cobertura de neutralización y potencia descrito a día de hoy. Su epítopo se localiza en una región próxima a...

Read more

Molecular mechanism for the subversion of the retromer coat by the Legionella effector RidL

01-02-2018

La legionelosis o enfermedad del legionario es una neumonía potencialmente fatal, causada por la bacteria Legionella pneumophila. Durante la infección, la bacteria trasloca un gran número de proteínas, llamadas efectores...

Read more

Late rDNA Condensation Ensures Timely Cdc14 Release and Coordination of Mitotic Exit Signaling with Nucleolar Segregation

01-01-2018

El nucléolo, además de su función esencial en la biogénesis de los ribosomas, juega también un papel importante en múltiples procesos celulares. Así, en este orgánulo se mantienen secuestradas proteínas clave para...

Read more

Inactivation of Capicua in adult mice causes T-cell lymphoblastic lymphoma

01-12-2017

CIC (also known as Capicua) is a transcriptional repressor negatively regulated by RAS/MAPK signaling. Whereas the functions of Cic have been well characterized in Drosophila, little is known about its...

Read more

Physical proximity of chromatin to nuclear pores prevents harmful R loop accumulation contributing to maintain genome stability

01-11-2017

During transcription, the mRNA may hybridize with DNA, forming an R loop, which can be physiological or pathological, constituting in this case a source of genomic instability. To understand the...

Read more

Whi7 is an unstable cell-cycle repressor of the Start transcriptional program

01-10-2017

Start is the main decision point in eukaryotic cell cycle in which cells commit to a new round of cell division. It involves the irreversible activation of a transcriptional program...

Read more

CTCF orchestrates the germinal centre transcriptional program and prevents premature plasma cell differentiation

01-09-2017

In germinal centres (GC) mature B cells undergo intense proliferation and immunoglobulin gene modification before they differentiate into memory B cells or long-lived plasma cells (PC). GC B-cell-to-PC transition involves...

Read more

Catalytic Cycle of the N-Acetylglucosaminidase NagZ from Pseudomonas aeruginosa

01-08-2017

The N-acetylglucosaminidase NagZ of Pseudomonas aeruginosa catalyzes the first cytoplasmic step in recycling of muropeptides, cell-wall-derived natural products. This reaction regulates gene expression for the β-lactam resistance enzyme, β-lactamase. The...

Read more

Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice.

01-07-2017

CREBBP is targeted by inactivating mutations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Here, we provide evidence from transgenic mouse models that Crebbp deletion results in deficits...

Read more

Local amplifiers of IL-4Rα-mediated macrophage activation promote repair in lung and liver

01-06-2017

The type 2 immune response controls helminth infection and maintains tissue homeostasis but can lead to allergy and fibrosis if not adequately regulated. We have discovered local tissue-specific amplifiers of...

Read more

Protector Members