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.

LXRα Promotes Hepatosteatosis in Part Through Activation of MicroRNA‐378 Transcription and Inhibition of Ppargc1β Expression

“…B). In part, because of its importance in regulating lipogenesis, we investigated whether Lxrα was able to modulate the transcription of Pri‐miR‐378 and Ppargc1β . The action of LXRα on the promoters of Ppargc1β and Pri‐miR‐378 was then examined by luciferase assay.…”

Phosphorylation of LXRα impacts atherosclerosis regression by modulating monocyte/macrophage trafficking

“…We 7 employed this strategy so plaques could develop normally under conditions of LXRα WT and then be switched to LXRα S196A to isolate the effect of LXR phosphorylation on regression (see Figure 2A for study protocol). Mice homozygous for LXRα S196A floxed allele (S196A FL/FL ) (18) with or without a tamoxifen inducible CRE recombinase (RosaCreER T2 ;CRE+ or CRE-) were used as donors for bone marrow (BM) transplantation into recipient Reversa mice (19). This is an Ldlr −/− model where the hyperlipidemia can be reversed after conditional inactivation of microsomal triglyceride transfer protein (Mttp) by pIpC treatment (Figure 2A).…”