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Role of SIRT1 and AMPK in the development of insulin resistance associated to non-alcoholic fatty liver disease
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Speaker:
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Marta Silvestre
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Author:
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M. Silvestre1*, M. Sugden1, B. Viollet2, M. Holness1
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Affiliation:
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1Centre for Diabetes, BICMS, Barts and the London, Queen Mary University of London, London, UK, 2Département Endocrinologie, Métabolisme et Cancer, Institut Cochin, Paris, France. *m.silvestre@qmul.ac.uk
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Background: Sirtuin 1 (SIRT1), a NAD+ dependent protein deacetylase, is important in modulating the hepatic response to fasting and caloric restriction. AMPK is activated in response to cellular stressors resulting in ATP depletion. Both enzymes can oppose the development of non-alcoholic fatty liver disease (NAFLD) by promoting lipid clearance AMPK is also known to interact with SIRT1 to modulate metabolism.
Aim: Our aim was to investigate the involvement of AMPK in the potential pathway that involves SIRT1 and AMPK in hepatic adaptions to fasting. To achieve this, gene expression was analysed in wild type (WT) and AMPK α1/2 liver-specific knockout mice (AMPK KO), following fasting and after a 4 h period of refeeding a carbohydrate-rich diet.
Results: As expected, hepatic gene expression of SIRT1, together with those of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), was significantly higher in fasted WT mice then in WT mice after refeeding. Gene expression levels of SIRT1, PEPCK and G6Pase were similar in refed WT mice and refed liver-specific AMPKα1/2-/- mice. In marked contrast, gene expression levels of SIRT1, PEPK and G6Pase were supressed in livers of fasted AMPKα1/2-/- mice compared with fasted WT mice. The effects of AMPK α1/2 deficiency to suppress SIRT1 gene expression following fasting was specific in that gene expression of the mitochondrial sirtuin, SIRT3, was similar in livers of liver-specific AMPK α1/2-/-.
Conclusions: These results demonstrate that AMPK has an obligatory role in augmentation of SIRT1 expression on fasting, and there is an associated impairment of the gluconeogenic profile of gene expression elicited by fasting. Since SIRT1 activity augments fatty acid oxidation, the data indicate that AMPK signalling to hepatic SIRT1 expression could be an important therapeutic target for fatty liver disease.
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