Fig. 2: Persistent ATF6α activation in hepatocytes induces liver injury and glucose metabolic dysfunction through FBP1 repression.
From: Activated ATF6α is a hepatic tumour driver restricting immunosurveillance
a, Schematic and liver images of TGAlb-cre− and TGAlb-cre+ mice euthanized aged 3 or 6 months. Scale bar, 1 cm. b,c, The liver-to-body weight (b) and serum ALT and AST levels (c) of 3- and 6-month-old TGAlb-cre− and TGAlb-cre+ mice. d, Representative liver TEM images of TGAlb-cre− and TGAlb-cre+ mice showing ER, mitochondria (M) and nucleus (N). Scale bar, 1 µm. Quantification is shown in Extended Data Fig. 2g. e, Representative immunoblot of liver lysates from 3-month-old TGAlb-cre− and TGAlb-cre+ mice. GAPDH was used as the loading control, run on a BiP blot. Quantification is shown in Extended Data Fig. 2i. f, Representative periodic acid–Schiff (PAS) staining and IHC for the indicated proteins in the livers of 3-month-old TGAlb-cre− and TGAlb-cre+ mice. Scale bar, 200 µm. Quantification is shown in Extended Data Fig. 2j. g–i, GSEA27 of liver RNA-seq (g), volcano plot of liver proteomic analysis (h) and NMR-based liver metabolic analysis (i) of 3-month-old TGAlb-cre+ versus TGAlb-cre− mice. EMT, epithelial-mesenchymal transition; FC, fold change; VIP score, variable importance score. j, CUT&RUN and ATAC–seq analysis of livers from 3-month-old TGAlb-cre+ versus TGAlb-cre− mice. Anti-IgG (control), anti-ATF6α (endogenous ATF6α) or anti-HA (exogenous nATF6α-HA) antibodies are indicated for CUT&RUN, while three JASPAR motifs aligning with the Fbp1 promoter predicted to bind to ATF6α motifs are shown. Hspa5 was used as the positive control. Rabepk is the neighbouring gene. k, Schematic of AAV8-gfp-, AAV8-cre- or AAV8-cre/fbp1-injected mice euthanized 3 weeks after injection, with liver images of TGAAV-cre and TGAAV-cre/fbp1 mice. Scale bar, 1 cm. l,m, The liver-to-body weight (l) and serum ALT levels (m) of TGAAV-gfp, TGAAV-cre and TGAAV-cre/fbp1 mice. n, Representative immunoblot of liver lysates from TGAAV-gfp, TGAAV-cre and TGAAV-cre/fbp1 mice. Vinculin was used as the loading control, run on a TRAPα blot. Quantification is shown in Extended Data Fig. 3d. o, Representative PAS staining and IHC for indicated proteins in TGAAV-cre and TGAAV-cre/fbp1 mouse livers. Scale bar, 200 µm. Quantification is shown in Extended Data Fig. 3e. p, GSEA27 of liver RNA-seq data from TGAAV-cre/fbp1 versus TGAAV-cre mice. Sample sizes, biological replicates and statistical tests are described in the Methods and Source data.
