Journal
CELL REPORTS
Volume 26, Issue 4, Pages 984-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.12.094
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Funding
- Medical Research Council [G0801278]
- British Heart Foundation [PG/13/10/30000, PG/16/87/32492]
- UCL Grand Challenges PhD Studentship
- Academy of Medical Sciences Newton Advanced Fellowship
- Royal Free Charity
- University of Oslo DIATECH@UiO initiative
- Centre for Innovative Medicine at the Karolinska Institute [CIMED-2-391/2016]
- Swedish Research Council [VR-2016-01743]
- Swedish Cancer Society [CAN-2015/609]
- Swedish Diabetes Foundation [DIA2016-157]
- Novo Nordisk Foundation [NN2017-21086]
- European Union FP7 HEALTH program [HUMAN-F5-2013-602757]
- NIH [R01HL117226]
- EPSRC [EP/L000296/1]
- Leverhulme Trust [RF-2015-482]
- Wellcome/EPSRC Centre for Interventional and Surgical Sciences grant [203145Z/16/Z]
- EPSRC [EP/L000296/1] Funding Source: UKRI
- MRC [G0801278] Funding Source: UKRI
- Swedish Research Council [2016-01743] Funding Source: Swedish Research Council
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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 (LXR alpha, 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 profibrotic and pro-inflammatory genes. Furthermore, S196A-LXR alpha expression reveals the regulation of novel diet-specific LXR alpha-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-LXR alpha phosphorylation acts as a novel nutritional molecular sensor that profoundly alters the hepatic H3K27 acetylome and transcriptome during NAFLD progression placing LXR alpha phosphorylation as an alternative anti-inflammatory or anti-fibrotic therapeutic target.
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