Fig. 4: Damaging mutations in LXRα cause liver injury in mice exposed to western diet despite suppression of lipogenesis.
a, The 8-week-old WT (LXRα+/+ or DN:WT, n = 15), heterozygous (LXRα+/W441R or DN:HET, n = 19) and homozygous (LXRαW441R/W441R or DN:HOM, n = 14) male mice were fed a western diet (WD) for 8 weeks. Created with biorender.com. b,c, After 8 weeks of western diet, 10 WT, 14 heterozygous and 10 homozygous mice were assessed for serum AST (b) and ALT (c) levels. d,e, Livers from these same mice were homogenized and assessed for level of triglycerides (d) and free cholesterol (e). f,g, Livers were also stained for 4-HNE (f) and collagen using PSR stain (g) and quantified by HALO. h, Representative images of PSR staining. We used mass spectrometry to assess the lipidome of WD and control diet-fed mice. i,j, Enrichment of lipid classes (i) and a heatmap focused on ether phospholipids (j). In a separate study, we repeated the experiment as in a, with WT (LXRα+/+ or KO:WT, n = 8), heterozygous (LXRα+/− or KO:HET, n = 8) and homozygous (LXRα−/− or KO:HOM, n = 8) mice. After killing at 16 weeks, RNA was extracted from the livers of all three genotypes from both studies and sequenced. k,l, Heatmap of RNA-seq expression data (n = 8) showing sample clustering based on the genes of Lipid Biosynthetic Process GO-annotation pathway (GO:0008610) (k), volcano plot of same genes (l). Two-sided P values are reported from Kruskal–Wallis test with Dunn’s multiple comparison test or ordinary one-way ANOVA with Holm–Šídak multiple comparison, based on the distribution of the data (b–g). All data are presented as mean ± s.d. CHL, cholesterol; TG, triglyceride; MG, monoglyceride; SM, sphingomyelin; S, sulfatides; GB3, GB gangliosides; CL, cardiolipin; GM1, GM1 gangliosides; DG, diglycerol; CE, cholesterol ester; PE, phosphatidylethanolamine; PC, phosphatidylcholine.
