RT Journal Article
SR Electronic
T1 Changes in LXRα phosphorylation promote a novel diet-induced transcriptome that alters the transition from fatty liver to steatohepatitis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 127779
DO 10.1101/127779
A1 Natalia Becares
A1 Matthew C Gage
A1 Lucia Martin Gutierrez
A1 Benoit Pourcet
A1 Oscar M Pello
A1 Tu Vinh Luong
A1 Saioa Goñi
A1 Ning Liang
A1 Cesar Pichardo
A1 Elina Shrestha
A1 Hanne-Røberg Larsen
A1 Vanessa Diaz
A1 Knut R. Steffensen
A1 Michael J. Garabedian
A1 Krista Rombouts
A1 Eckardt Treuter
A1 Inés Pineda-Torra
YR 2017
UL http://biorxiv.org/content/early/2017/04/15/127779.abstract
AB Understanding the transition from fatty liver or steatosis to more advanced inflammatory and fibrotic stages of non-alcoholic fatty liver disease (steatohepatitis), is key to define strategies that alter or even reverse the progression of this pathology. The Liver X Receptor alpha (LXRα) controls hepatic lipid homeostasis and inflammation. Here we show that mice carrying a mutation that abolishes phosphorylation at Ser196 (S196A) in LXRα exhibit reduced hepatic inflammation and fibrosis when challenged with a high fat-high cholesterol diet, despite displaying enhanced hepatic lipid accumulation. This protective effect is associated with reduced cholesterol accumulation, a key promoter of lipid-mediated hepatic damage. Reduced steatohepatitis in S196A mice involves the reprogramming of the liver transcriptome by promoting diet-induced changes in the expression of genes involved in endoplasmic reticulum stress, extracellular matrix remodelling, inflammation and lipid metabolism. Unexpectedly, changes in LXRα phosphorylation uncover novel diet-specific target genes, whose regulation does not simply mirror ligand-induced LXR activation. These unique LXRα phosphorylation-sensitive, diet-responsive target genes are revealed by promoting LXR occupancy and cofactor recruitment in the context of a cholesterol-rich diet. Therefore, LXRα phosphorylation at Ser196 critically acts as a novel nutritional sensor that promotes a unique diet-induced transcriptome thereby modulating metabolic, inflammatory and fibrotic responses important in the transition to steatohepatitis.