Fig. 5: OGA inhibition reduced hyperammonemia in mouse models of both inherited and acquired liver diseases. | Nature Communications

Fig. 5: OGA inhibition reduced hyperammonemia in mouse models of both inherited and acquired liver diseases.

From: O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis

Fig. 5

a Blood ammonia in Pcca−/− (A138T) mice injected with Thiamet-G (40 mg/kg for 5 days) (n = 12) or vehicle (n = 10). Age-matched C57BL/6 wild-type (WT) untreated mice were used as controls (n = 12). p = 0.00002, p = 0.0097 (one-way ANOVA). b Ratio of propionylcarnitine (C3) to acetylcarnitine (C2) in sera of Pcca−/− (A138T) mice treated with Thiamet-G (n = 8) or vehicle (n = 9). Age-matched WT untreated mice were used as controls (n = 12) (One-way ANOVA). c Increased O-GlcNAcylation of CPS1 in livers of Pcca−/− (A138T) mice i.p. injected with Thiamet-G. Samples were run on the same gel but were non-contiguous. d Blood ammonia in WT mice treated with Thiamet-G (40 mg/kg, i.p. for 5 days) and/or thioacetamide (TAA; 250 mg/kg, i.p. 24 h before sacrifice) or with vehicle. Thiamet-G + TAA n = 9; Vehicle + TAA n = 8, Vehicle untreated n = 4. p = 0.002, p = 0.024 (One-way ANOVA). e Serum alanine transaminase (ALT) in WT mice treated with Thiamet-G and/or TAA or with vehicle. Thiamet-G + TAA n = 9; Vehicle + TAA n = 8, Vehicle untreated n = 4. f Increased O-GlcNAcylation of CPS1 in livers of TAA-treated mice i.p. injected with Thiamet-G. g Model for CPS1 O-GlcNAcylation in ureagenesis. Under normal conditions: ammonia is cleared by the synthesis of urea through the urea cycle and CPS1 is the rate-limiting step. During hyperammonemia, increased availability of UDP-GlcNAc is associated with greater O-GlcNAcylation of CPS1, enhanced enzyme catalytic efficiency for ammonia and overall ureagenesis, thus resulting in increased ammonia detoxification. Enhancement of CPS1 O-GlcNAcylation by Thiamet-G-mediated inhibition of OGA can be exploited to reduce hyperammonemia. All values are shown as averages ± SEM. ns, no statistically significant difference. Experiments in panels c and f were performed twice.

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