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Impaired LXRα Phosphorylation Attenuates Progression of Fatty Liver Disease.

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2019

Cell Rep. 2019 Jan 22;26(4):984-995.e6. doi: 10.1016/j.celrep.2018.12.094.

Impaired LXRα Phosphorylation Attenuates Progression of Fatty Liver Disease.

N Becares;MC Gage;M Voisin;E Shrestha;L Martin-Gutierrez;N Liang;R Louie;B Pourcet;OM Pello;TV Luong;S Goñi;C Pichardo-Almarza;H Røberg-Larsen;V Diaz-Zuccarini;KR Steffensen;A O'Brien;MJ Garabedian;K Rombouts;E Treuter;I Pineda-Torra

Centre of Cardiometabolic Medicine, Division of Medicine, University College of London, London WC1 E6JF, UK. Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA. Karolinska Institute, Centre for Innovative Medicine (CIMED), Department of Biosciences and Nutrition, 14183 Huddinge, Sweden. Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London NW3 2QG, UK. Department of Mechanical Engineering, University College London, London WC1E 7JE, UK. Department of Chemistry, University of Oslo, 0371 Oslo, Norway. Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institute, 14186 Huddinge, Sweden. Institute for Liver & Digestive Health, University College London, Royal Free, London NW3 2PF, UK. Centre of Cardiometabolic Medicine, Division of Medicine, University College of London, London WC1 E6JF, UK.

Service type: Knock-in mice

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a very common indication for liver transplantation. How fat-rich diets promote progression from fatty liver to more damaging inflammatory and fibrotic stages is poorly understood. Here, we show that disrupting phosphorylation at Ser196 (S196A) in the liver X receptor alpha (LXRα, NR1H3) retards NAFLD progression in mice on a high-fat-high-cholesterol diet. Mechanistically, this is explained by key histone acetylation (H3K27) and transcriptional changes in pro-fibrotic and pro-inflammatory genes. Furthermore, S196A-LXRα expression reveals the regulation of novel diet-specific LXRα-responsive genes, including the induction of Ces1f, implicated in the breakdown of hepatic lipids. This involves induced H3K27 acetylation and altered LXR and TBLR1 cofactor occupancy at the Ces1f gene in S196A fatty livers. Overall, impaired Ser196-LXRα phosphorylation acts as a novel nutritional molecular sensor that profoundly alters the hepatic H3K27 acetylome and transcriptome during NAFLD progression placing LXRα phosphorylation as an alternative anti-inflammatory or anti-fibrotic therapeutic target.

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