Fluvastatin Causes NLRP3 Inflammasome-Mediated Adipose Insulin Resistance
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Figures
- Figure 1
Statins activate the NLRP3 inflammasome in macrophages. A: BMDMs from WT mice were treated with various statins (10 μmol/L, 18 h) and/or LPS (200 ng/mL, 4 h), and IL-1β in the media was quantified. BMDMs were treated with various doses of fluvastatin and/or LPS, and IL-1β (B) and IL-6 (C) in the media were quantified. D: BMDMs were treated with LPS, and 1 μmol/L fluvastatin combined with vehicle or 10 μmol/L GGPP and IL-1β in the media was quantified. E: BMDMs were treated with LPS, and 1 μmol/L fluvastatin combined with vehicle, or 10 μmol/L z-WHED-FMK, or 200 μmol/L glyburide and IL-1β in the media was quantified. Transcript levels of cytokines (F) and PRRs (G) in BMDMs after 1 μmol/L fluvastatin (18 h) and 200 ng/mL LPS (4 h) treatment. BMDMs from NLRP3−/− mice were treated with various doses of fluvastatin and/or 200 ng/mL LPS, and IL-1β (H) and IL-6 (I) in the media were quantified. *Significantly different from LPS alone or as indicated by connecting bars; ϕsignificantly different from conditions without LPS; #significantly different from fluvastatin plus LPS; ^significantly different from control or statin alone. Statin, fluvastatin. Values are shown as the mean ± SEM. n > 3 for all conditions.
- Figure 2
Fluvastatin activates the NLRP3 inflammasome and impairs insulin signaling in adipose tissue. A: In vivo insulin-stimulated 2DG uptake in BAT and WAT from ob/ob mice orally treated with vehicle (Control) or fluvastatin (Statin) for 6 weeks (n ≥ 3 mice per group). Caspase-1 (B) and caspase-3 (C) activity in adipose tissue explants from WT mice and NLRP3−/− mice, where explants (n > 7) were treated with vehicle (control), LPS (2 μg/mL) plus 10 μmol/L fluvastatin (L+S) or L+S plus 10 μmol/L glyburide (L+S+Glyb). D: Quantification of IL-1β in adipose tissue lysates from WT and NLRP3−/− mice after treatment of explants with vehicle (control), LPS, fluvastatin, or LPS plus fluvastatin. E: Representative immunoblots (left) and quantification (right) of basal (Bas; i.e., no insulin) and insulin-mediated pAkt (serine 473) after treatment with fluvastatin and/or LPS in adipose tissue explants (n > 6) from WT and NLRP3−/− mice. F: Representative immunoblots (left) and quantification (right) of basal and insulin-mediated phosphorylation of Akt after treatment with fluvastatin and LPS with various doses of glyburide in adipose tissue explants from WT mice. ϕSignificantly different from control or basal; εsignificantly different from L+S; ^significantly different from LPS alone in WT; #significantly different from vehicle control (with insulin). Statin, fluvastatin. Values are shown as the mean ± SEM. n ≥ 8 explants per group. AU, arbitrary units.
- Figure 3
Cell-autonomous actions of fluvastatin in adipocytes. Time course (A) and quantification (B) of relative caspase-1 activity in 3T3-L1 adipocytes after treatment with vehicle (Control) or LPS plus fluvastatin (L+S) (n ≥ 7/group). Quantification of IL-1β (C) and IL-6 (D) secreted in the media after control or L+S (n ≥ 8/group). E: Representative immunoblots (left) and quantification (right) of 0.3 and 100 nmol/L insulin-stimulated phosphorylation of Akt (serine 473) in 3T3-L1 adipocytes after treatment with control or L+S (n = 4/group). *Significantly different from control (no insulin); #significantly different from control at the same dose of insulin. AU, arbitrary units; Con, control; nd, not detected; Statin, fluvastatin. Values are shown as the mean ± SEM.
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