Fig. 4: While Gpx4 overexpression has no effect, CDAHFD-induced MASH protects against loss of hepatocyte Gpx4. | Cell Death & Differentiation

Fig. 4: While Gpx4 overexpression has no effect, CDAHFD-induced MASH protects against loss of hepatocyte Gpx4.

From: Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease

Fig. 4

Role of glutathione peroxidase 4 (Gpx4) in choline-deficient L-amino acid-defined diet (CDAHFD) was explored using transgenic mice with whole-body GPX4 overexpression (Gpx4Tg/+) or tamoxifen-inducible hepatocyte-specific Gpx4 knockout (Gpx4fl/fl AlbCreERT2Tg/+). A Western blot for hepatic Gpx4 in Gpx4Tg/+ and wild-type littermates (Gpx4+/+) fed CDAHFD or standard diet (SD). B, C Hepatic MDA and reduced glutathione (GSH) normalized for protein content (n = 6 or 8). D Experimental design for hepatocyte-specific Gpx4 knockout (n = 5 or 7). E Kaplan–Meier curves of Gpx4fl/fl AlbCreERT2Tg/+ fed SD or CDAHFD; day 0 equals first day of tamoxifen. F Western blot of hepatic Gpx4 in Gpx4fl/fl AlbCreERT2Tg/+ (brackets) and controls (Gpx4fl/fl AlbCreERT2+/+, without brackets) after tamoxifen. G H&E stain of Gpx4fl/fl AlbCreERT2Tg/+ and controls fed SD or CDAHFD at spontaneous morbidity or experiment termination. Magnification 100×, scale bar 200 µm. H Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST). I Mass spectrometry for hepatic vitamin E, ratios of reduced-on-oxidized glutathione (GSH/GSSG), tetrahydrobiopterin-on-7,8-dihydro-L-biopterin (BH4/BH2) and oxidized-on-reduced nicotinamide adenine dinucleotide (NADH/NAD). Data from two independent experiments, mean ± standard deviation. Scale bar 200 µm. *p < 0.05; **p < 0.01; ***p < 0.001; #p < 0.05 for factor diet; §p < 0.05 for factor genotype. Log-rank test, two-way ANOVA with post-hoc test.

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