Fig. 2: The transcriptional response of the liver to sustained dyslipidemia.

a, Heat maps of bulk mRNA-seq of whole liver showing the 72 significant differentially expressed genes common to both dyslipidemic strains versus respective littermate controls after 8 weeks, 12 weeks and 20 weeks on an HFD (n = 2–5). b, Expression of the 72 conserved genes in liver cells using clusters taken from ref. ¹⁹. c, Pie chart showing how expression of the 72 conserved genes correlates with PCSK9 transcript levels in human liver samples (n = 261). d, Correlations with human PCSK9 levels for 12 of the 34 positively correlating genes from c. e, Representative ORO liver sections (top) and confocal images of F4/80 immunofluorescence (bottom) in the livers of D374Y dyslipidemic mice treated with clodronate liposomes and Dil liposomes (control) for 8 weeks while on an HFD (scale bar, 100 μm; n = 2 D3747 control and n = 2 D3747 clodronate, where every n represents a different mouse). f, Effect of long-term administration of clodronate liposomes on the 72 differentially expressed genes (n = 2–3). g, Top, percentages of blood and liver monocytes (live CD45⁺CD19⁻CD3e⁻CD64⁻Ly6C⁺) and liver KCs (live CD45⁺CD19⁻CD3e⁻CD64⁺Ly6C⁻F4/80⁺TIM4⁺) in D374Y dyslipidemic mice after 8 weeks of treatment with clodronate liposomes (n = 2 D374Y clodronate and n = 3 D374Y control mice). Bottom, heat maps showing variations in the expression of signature genes for KCs, monocytes, LAMs and CD207⁺ macrophages in the liver of D374Y mice after long-term clodronate exposure (n = 2 D374Y clodronate and n = 3 D374Y control mice). h, Transcript per million values for a clodronate-sensitive gene (Cd5l) and a clodronate-insensitive gene (Ctsd) from D374Y and littermate control and D374Y treated with Dil liposomes or clodronate liposomes (n = 3 littermate control, n = 5 D374Y, n = 3 D374Y control and n = 2 D374Y clodronate mice). i, Total liver cholesterol (mg) in D374Y dyslipidemic mice treated with either clodronate liposomes or Dil liposomes for 8 weeks while on an HFD (n = 2 D374Y clodronate and n = 3 D374Y control mice). j, Plasma levels of IL18BP (ng ml⁻¹) after 8 weeks on an HFD in dyslipidemic APOE cKO and D374Y mice versus respective littermate controls (n = 5 APOE cKO and n = 3 littermate control mice; n = 5 D374Y and n = 5 littermate control mice). All plots are ±s.e.m. Two-sided t-test (g,i,j). cDC, conventional dendritic cell; HSPC, hematopoietic stem and progenitor cell; ILC, innate lymphoid cell; Macs, macrophages; Mig., migratory; NK, natural killer; pDC, plasmacytoid dendritic cell.