Extended Data Fig. 7: AMPK is required for aldometanib to alleviate fatty liver and NASH.
From: The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK
a, aldometanib impairs post-prandial TAG absorption. The HFD-induced obese mice were starved for 8 h, followed by injection with Tyloxapol and gavaged with aldometanib. Some 0.5 h later, mice were gavaged with 10 ml/kg olive oil, followed by determining serum TAG. Data are mean ± s.e.m., n = 6 mice for each treatment, and P value by two-way ANOVA followed by Sidak (TAG). b, c, aldometanib does not change faecal lipid content. The HFD-induced obese mice were gavaged with aldometanib. At 1 h after gavaging, levels of faecal TAG (b) and long-chain fatty acids (c) were determined. Data are mean ± s.e.m., n = 9 (b, Veh), 7 (b, 2 mpk; c, Veh), and 6 (c, 2 mpk) mice for each treatment, and P value by two-sided Student’s t-test. d, The 1-month treatment of aldometanib administration does not change ambulatory activity. Experiments were performed as in Fig. 6d. Data are shown as box-and-whisker plots (n = 8 mice, P values by two-way ANOVA, followed by Tukey). e, Hepatic knockout of AMPK impairs the effects of 1-month aldometanib treatment in reducing hepatic TAG; experiments as in Fig. 5c, but using AMPKα-LKO mice. f, i, aldometanib promotes AMPK activation in the liver of obese and NASH mouse models. HFD-induced obese mice (f) and the AMLN-NASH mice (i) were gavaged with aldometanib, followed by determining AMPK activation in liver tissues 2 h after gavaging. g, h, Hepatic knockout of AMPK impairs the effects of aldometanib in alleviating NASH. Mice were treated as in Fig. 7a, followed by measuring serum AST (g, left panel), ALP (g, middle panel), ALT (g, right panel), insulin levels during the ipGTT (h, left panel), and performing ITT (h, right panel). Data are mean ± s.e.m.; n = 8 (g), 4 (h, left panel) or 5 (h, right panel) mice for each genotype/treatment, and P value by two-way (g, AUC of h), two-way RM (glucose of h) ANOVA, followed by Tukey (labelled as in Fig. 3i). Experiments in this figure were performed three times.
