Fig. 4: Elevated IL-1β leads to HNF4α-mediated suppression of A1AT expression in hepatocytes.

a, Relative mRNA expression of Serpina1c-e in hepatocytes treated with palmitic acid, oleic acid (PO) and hydrogen peroxide (H₂O₂). b, scRNA-seq analysis of NPCs from the NCD- and FFD-fed mice. Visualization of the scRNA-seq data highlighting the gene expression patterns of the cytokines Tnf, Il1b and Il6. c, A violin plot visualization of the scRNA-seq data, highlighting the gene expression patterns of the cytokines Tnf, Il1b and Il6 in different cell types. d, Relative expression of Serpina1c-e mRNA in hepatocytes treated with CM from LPS-simulated (CM-KC-LPS) or untreated KCs (CM-KC-Control). e, Relative expression of Serpina1c-e mRNA in primary hepatocytes treated with recombinant TNF, IL-6 and IL-1β proteins. All recombinant proteins were treated at 100 ng/ml, for 24 h. f, A volcano plot of differential mRNA expression between the IL-1β recombinant protein-treated group and the untreated group (control). The selected genes with P values (P < 0.05) and fold changes (>1.5) are labeled with green/red dots reflecting down-/upregulated genes. g, Prediction of SERPINA1 gene promoter-binding transcription factors via PROMO software (version 3.0.2) with 3,000 bp upstream to 3000 bp downstream of the SERPINA1 transcription initiation site (TSS) located in the promoter region. h, A Venn diagram indicating the integration of the differentially expressed genes (DEGs) (f) and prediction of transcription factors (g). i, Relative mRNA expression of Serpina1 gene transcription factor candidates (Hif1a and Hnf4a) in hepatic tissue samples from NCD- and FFD-fed mice. j, mRNA expression levels of HIF1A and HNF4A in human hepatic tissues were analyzed via publicly available human liver RNA-seq datasets in the GEO database (GSE48452 and GSE61260). k, Protein levels of HIF1α, HNF4α and A1AT in hepatocytes treated with recombinant IL-1β protein or untreated hepatocytes (control). l, Primary hepatocytes isolated from marmosets were stimulated with IL-1β for 48 h. Protein expression of A1AT and HNF4α was detected. m, Relative protein expression of A1AT in HepG2 cells transfected with siHIF1a, siHNF4a or the siNegative control (siNeg.). n, Browser track showing HNF4A (from GSM469863 and GSM469864) and H3K4me4 (GSM2534178 and GSM2534179) ChIP-seq data in the SERPINA1 region. Pink highlights depict the SERPINA1 variant 1 promoter. o, The binding affinity of HNF4α for the SERPINA1 promoter in HepG2 cells was investigated via a ChIP assay. This involved the use of an HNF4α antibody and an IgG control. Additionally, RT‒PCR experiments were conducted with various primer combinations to further examine this interaction. The data are presented as the means ± s.d.; *^,#P < 0.05, **^,##P < 0.01, ***^,###P < 0.001 and ****^,####P < 0.0001 versus the control model. ns, not significant.