title: Liver-Specific Activation of AMPK Prevents Steatosis on a High-Fructose Diet.
abstract: AMP-activated protein kinase (AMPK) plays a key role in integrating metabolic pathways in response to energy demand. We identified a mutation in the γ1 subunit (γ1D316A) that leads to activation of AMPK. We generated mice with this mutation to study the effect of chronic liver-specific activation of AMPK in vivo. Primary hepatocytes isolated from these mice have reduced gluconeogenesis and fatty acid synthesis, but there is no effect on fatty acid oxidation compared to cells from wild-type mice. Liver-specific activation of AMPK decreases lipogenesis in vivo and completely protects against hepatic steatosis when mice are fed a high-fructose diet. Our findings demonstrate that liver-specific activation of AMPK is sufficient to protect against hepatic triglyceride accumulation, a hallmark of non-alcoholic fatty liver disease (NAFLD). These results emphasize the clinical relevance of activating AMPK in the liver to combat NAFLD and potentially other associated complications (e.g., cirrhosis and hepatocellular carcinoma).
authors.affiliation: MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. Electronic address: angela.woods@lms.mrc.ac.uk.
authors.forename: Angela
authors.initials: A
authors.lastname: Woods
authors.affiliation: MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Jennet R
authors.initials: JR
authors.lastname: Williams
authors.affiliation: MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Muckett
authors.affiliation: MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Faith V
authors.initials: FV
authors.lastname: Mayer
authors.affiliation: Drug Safety and Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Liljevald
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, Sweden.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Bohlooly-Y
authors.affiliation: MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital, London W12 0NN, UK; Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. Electronic address: david.carling@lms.mrc.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Carling
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004032:Diet; D000073417:Dietary Sugars; D004789:Enzyme Activation; D005632:Fructose; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D065626:Non-alcoholic Fatty Liver Disease / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D009928:Organ Specificity
chemical_list: D000073417:Dietary Sugars; D005632:Fructose; D055372:AMP-Activated Protein Kinases
keywords: AMPK; NAFLD; fructose; lipogenesis; liver disease; steatosis