Impaired LXRα Phosphorylation Attenuates Progression of Fatty Liver Disease | Zendy

Natalia Bécares | Zendy; Matthew Gage | Zendy; Maud Voisin | Zendy; Elina Shrestha | Zendy; Lucia MartinGutierrez | Zendy; Ning Liang | Zendy; Rikah Louie | Zendy; Benoît Pourcet | Zendy; Óscar M. Pello | Zendy; Tu Vinh Luong | Zendy; Saioa Goñi | Zendy; César PichardoAlmarza | Zendy; Hanne RøbergLarsen | Zendy; Vanessa DíazZuccarini | Zendy; Knut R. Steffensen | Zendy; Alastair O’Brien | Zendy; Michael J. Garabedian | Zendy; Krista Rombouts | Zendy; Eckardt Treuter | Zendy; Inès PinedaTorra | Zendy

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Impaired LXRα Phosphorylation Attenuates Progression of Fatty Liver Disease

Author(s) -

Natalia Bécares,

Matthew Gage,

Maud Voisin,

Elina Shrestha,

Lucia MartinGutierrez,

Ning Liang,

Rikah Louie,

Benoît Pourcet,

Óscar M. Pello,

Tu Vinh Luong,

Saioa Goñi,

César PichardoAlmarza,

Hanne RøbergLarsen,

Vanessa DíazZuccarini,

Knut R. Steffensen,

Alastair O’Brien,

Michael J. Garabedian,

Krista Rombouts,

Eckardt Treuter,

Inès PinedaTorra

Publication year - 2019

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2018.12.094

Subject(s) - liver x receptor , fatty liver , phosphorylation , biology , acetylation , histone h3 , transcriptome , endocrinology , medicine , cancer research , microbiology and biotechnology , gene expression , biochemistry , nuclear receptor , gene , disease , transcription factor

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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