Changes in LXRα phosphorylation promote a novel diet-induced transcriptome that alters the transition from fatty liver to steatohepatitis

Abstract

SUMMARYUnderstanding the transition from fatty liver (steatosis) to inflammatory and fibrotic steatohepatitis, is key to define strategies that alter its progression. Here we show that, when challenged with a high fat-high cholesterol diet, mice carrying a mutation that abolishes phosphorylation at Ser196 (S196A) in the liver X receptor alpha (LXRα) exhibit reduced hepatic inflammation and fibrosis despite displaying enhanced steatosis. This is associated with a marked protection against cholesterol accumulation. Reduced steatohepatitis in S196A mice involves unique reprogramming of the liver transcriptome in response to the diet. Remarkably, impaired LXRα phosphorylation uncovers novel diet-specific/phosphorylation-sensitive genes, whose regulation does not simply mirror ligand-induced LXR activation. Regulation of these unique, dually responsive genes, is associated with the promotion of LXR and cofactor occupancy under a cholesterol-rich diet. Therefore, Ser196-LXRα phosphorylation acts as a novel nutritional sensor that triggers a unique diet-induced transcriptome, thereby modulating metabolic, inflammatory and fibrotic responses important in the transition to steatohepatitis.