Fig. 6: Hepatocyte-specific deletion of BAX/BAK reduces expression of RNA sensors and inflammation in the liver during MASH. | Nature Communications

Fig. 6: Hepatocyte-specific deletion of BAX/BAK reduces expression of RNA sensors and inflammation in the liver during MASH.

From: Mitochondrial RNA cytosolic leakage drives the SASP

Fig. 6: Hepatocyte-specific deletion of BAX/BAK reduces expression of RNA sensors and inflammation in the liver during MASH.The alternative text for this image may have been generated using AI.

a Schematic of experimental design: wild-type mice (10–12 weeks old) were fed either standard chow or a high-fat, fructose, and cholesterol (FFC) diet for 24 weeks to induce metabolic-associated steatohepatitis (MASH). b Western blot showing levels of the senescence marker p21 in liver tissue from chow- and FFC-fed mice. c Quantification of p21 protein levels from the Western blot shown in (b). n = 5 mice per group. d Quantification of telomere-associated DNA damage foci (TAF) in liver sections from chow- and FFC-fed mice, shown as mean TAF per nucleus. n = 5 mice per group. e Quantification of the percentage of MAVS/RIG-I double-positive puncta per field in liver sections from chow- and FFC-fed mice, measured by Proximity Ligation Assay (PLA). n = 5 chow- and 3 FFC-fed mice. f Representative PLA images. Scale bar = 30 μm. mRNA expression levels of g cytosolic RNA sensors, h SASP-related factors and i immune cell markers, Cd45 and Cd68 in the livers from chow and FFC-fed mice. n = 7 mice per group. j Experimental setup for hepatocyte-specific Bak and Bax deletion. Bak−/− Baxfl/fl mice (10–12 weeks old) were fed an FFC diet for 16 weeks to induce MASH. Mice were then injected with either AAV8-GFP (control) or AAV8-TBG-Cre virus via the tail vein to induce deletion of Bax specifically in hepatocytes. k Western blot showing successful deletion of Bax in the liver following AAV8-TBG-Cre injection. n = 3-4 mice per group. qPCR quantification of l Bax, m markers of fibrosis and n RNA sensors in livers of FFC-fed Bak−/− Baxfl/fl and Bak−/− Bax−/− mice. n = 5 mice per group. o Gene ontology (GO) term enrichment analysis showing pathways related to inflammation that are significantly altered between livers from FFC-fed Bak−/− Baxfl/fl (n = 3) and Bak−/− Bax−/− (n = 4) mice. p Column-clustered heatmap of significantly downregulated inflammation-related genes in the livers of FFC-fed mice lacking both Bax and Bak. Color intensity reflects column Z-score of gene expression. q Gene set enrichment analysis (GSEA) showing negative enrichment scores for both RIG-I–like receptor signaling and cytosolic DNA sensing pathways in Bak−/− Bax−/− livers. Data are mean ± s.e.m. Statistical significance was assessed by a two-sided Student’s unpaired t-test (c, d, g, i, l, m) and a Nested t-test (h, n). c p = 0.0007; d 0.0413; e p = 0.0416; g p = 0.0114, p = 0.0284, p < 0.0001; h p = 0.0287; i p < 0.0001, p < 0.0001; l p < 0.0001; m p = 0.0436, p = 0.06, p = 0.0118; (n) p < 0.0001. a, j Created in BioRender. Victorelli, S. (2025) https://BioRender.com/tdsqpjz.

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