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Regulation of hepatic metabolism by the autophagic protein TP53INP2

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Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular

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[eng] Decreased physical activity and increased consumption of energy-rich food are hallmark lifestyle modifications that developed and amplified over the course of only a few decades. These changes in our daily behavior are the culprits for the rise of various metabolic diseases, collectively regarded to as the metabolic syndrome, that has reached the magnitude of a global epidemic.
The hepatic manifestation of the metabolic syndrome is the non-alcoholic fatty liver disease (NAFLD), and it is estimated to affect every third adult person by 2030. Although considered relatively benign, NAFLD can progress to more severe liver diseases, up to the point of liver failure, through insufficiently understood processes. Different studies have shown a connection between autophagy and the development of steatosis. However, the different genetic models used in those studies report that steatosis can be ameliorated or enhanced by impaired autophagy and is dependent on the model as well as the experimental conditions.
In the present project we aimed to analyze the impact of liver-specific depletion of a positive regulator of autophagy termed TP53INP2 on liver metabolism and delineate its potential role in the development of steatosis.
We found that the hepatic expression of TP53INP2 in mice is modulated by nutrient deprivation as well as the presence of abundant nutrients. Mice specifically lacking TP53INP2 in the liver, show impaired hepatic free fatty acid oxidation and ketogenesis, evoked from a compromised transcriptional activity of the transcription factors PPARα and LXRα. We have observed that the hepatocyte-specific ablation of TP53INP2 enhances fasting- and dietary-induced steatosis and impacts cholesterol and bile acid metabolism upon consumption of diets rich in lipids and cholesterol. Furthermore, we have detected a role of TP53INP2 in the release of cholesterol from lysosomes, potentially involving the lysosome-associated membrane protein 1 (LAMP1).
 
Together, our data indicate that TP53INP2 is a key regulator of hepatic lipid metabolism through the modulation of PPARα and LXRα activity. We propose that such a modulation relies on the promotion of ligand availability, perhaps dependent of autophagy.

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Tesis Doctorals - Departament - Bioquímica i Biomedicina Molecular

# metadata.dc.title[].value
Regulation of hepatic metabolism by the autophagic protein TP53INP2