• Home
  • Search Results
  • Impaired LXRα Phosphorylation Attenuates Progression of Fatty Liver Disease.

Impaired LXRα Phosphorylation Attenuates Progression of Fatty Liver Disease.

Cell reports (2019-01-24)
Natalia Becares, Matthew C Gage, Maud Voisin, Elina Shrestha, Lucia Martin-Gutierrez, Ning Liang, Rikah Louie, Benoit Pourcet, Oscar M Pello, Tu Vinh Luong, Saioa Goñi, Cesar Pichardo-Almarza, Hanne Røberg-Larsen, Vanessa Diaz-Zuccarini, Knut R Steffensen, Alastair O'Brien, Michael J Garabedian, Krista Rombouts, Eckardt Treuter, Inés Pineda-Torra
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal ANTI-FLAG® M2 antibody produced in mouse, clone M2, purified immunoglobulin (Purified IgG1 subclass), buffered aqueous solution (10 mM sodium phosphate, 150 mM NaCl, pH 7.4, containing 0.02% sodium azide)
Supelco
Supelco 37 Component FAME Mix, certified reference material, TraceCERT®, in dichloromethane (varied conc.), ampule of 1 mL
Sigma-Aldrich
Monoclonal Anti-α-Tubulin antibody produced in mouse, ascites fluid, clone B-5-1-2
Sigma-Aldrich
N-Chlorosuccinimide, 98%
Sigma-Aldrich
IgG from rabbit serum, reagent grade, ≥95% (SDS-PAGE), essentially salt-free, lyophilized powder
Sigma-Aldrich
Di(N-succinimidyl) glutarate, ≥97.0% (CHN)
Sigma-Aldrich
T0901317, ≥98%