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2011/01/20

Prohibiting hepatocytes to lose control

 

Hepatocellular carcinoma (HCC) is the most frequent primary malignant tumor type in the liver. Whereas the etiology frequently involves viral infection or alcoholic cirrhosis, it can often be preceded by non-alcoholic steatohepatitis (NASH). Critically, Non-Alcoholic Fatty Liver Disease (NAFLD) is present in up to a third of the general population. It is therefore of tremendous interest to characterise the biological factors that affect the pathogenesis of NASH and HCC.


Researchers at CIC bioGUNE have contributed extensively to the understanding the effect of altered methionine metabolism on NASH and HCC development. Using their newly generated, elegant mouse models, Mato and co-workers have defined the metabolic tumor suppression activity of key components of this pathway, namely MAT1A (methionine adenosyl transferase 1A) and GNMT (glycine-N-methyltransferase). In previous studies, they had demonstrated that the development of NASH and HCC in Mat1a knockout mice correlates with the down-regulation of Prohibitins, which participate in a variety of cellular processes, including mitochondrial chaperone, growth and apoptosis. In the search for a function of Prohibitin in liver physiology, the authors used a liver-specific Prohibitin 1(Phb1) conditional knockout mouse. These mice exhibit liver damage, proliferation and apoptosis at an early age, followed by the development of aggressive multifocal HCC. The tumor suppression activity of PHB1 was further corroborated in vitro in human hepatocytes and supported by the observation that human hepatoma cell lines exhibit reduced PHB1 levels. Mechanistically, reduction of PHB1 levels affected the activity of the transcription factor E2F, leading to increased E2F target genes expression, including the mitogenic Cyclin D1.


These findings strongly suggest that down-regulation of PHB1 upon MAT1A loss is a causal event in the development of HCC but not in NASH. Further research will be needed to define the drivers of NASH and HCC and the factors implicated in the transition between these two complex disease states.



Arkaitz Carracedo

Hepatology, Vol. 52, No. 6, 2010, PMID: 20890892

2011/01/20

Liver-specific deletion of prohibitin 1 results in spontaneous liver injury, fibrosis, and...

 Prohibitin 1 is a highly conserved, ubiquitously expressed protein that participates...

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2011/01/26

Javier Conde Vancells defends his PhD thesis on February 2nd, 2011

Javier Conde Vancells will defend his PhD thesis, entitled "Molecular and Functional Study of Exosome-like...

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