Changes in LXRα phosphorylation promote a novel diet-induced transcriptome that alters the transition from fatty liver to steatohepatitis
| Autor: | Elina Shrestha, Benoit Pourcet, Pichardo C, R. Louie, Ines Pineda-Torra, T.V. Luong, Diaz, Natalia Becares, Krista Rombouts, Pello Om, Hanne Roberg-Larsen, Michael J. Garabedian, Eckardt Treuter, Matthew C. Gage, Lucia Martin-Gutierrez, Ning Liang, Knut R. Steffensen, Goñi S |
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| Rok vydání: | 2017 |
| Předmět: |
0303 health sciences
medicine.medical_specialty Fatty liver Liver X receptor alpha Lipid metabolism Biology medicine.disease Transcriptome 03 medical and health sciences 0302 clinical medicine Endocrinology 030220 oncology & carcinogenesis Internal medicine medicine Phosphorylation Steatohepatitis Steatosis Liver X receptor 030304 developmental biology |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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