Fluvastatin Causes NLRP3 Inflammasome-Mediated Adipose Insulin Resistance

Abstract

Statins reduce lipid levels and are widely prescribed. Statins have been associated with an increased incidence of type 2 diabetes, but the mechanisms are unclear. Activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3)/caspase-1 inflammasome, promotes insulin resistance, a precursor of type 2 diabetes. We showed that four different statins increased interleukin-1β (IL-1β) secretion from macrophages, which is characteristic of NLRP3 inflammasome activation. This effect was dose dependent, absent in NLRP3−/− mice, and prevented by caspase-1 inhibition or the diabetes drug glyburide. Long-term fluvastatin treatment of obese mice impaired insulin-stimulated glucose uptake in adipose tissue. Fluvastatin-induced activation of the NLRP3/caspase-1 pathway was required for the development of insulin resistance in adipose tissue explants, an effect also prevented by glyburide. Fluvastatin impaired insulin signaling in lipopolysaccharide-primed 3T3-L1 adipocytes, an effect associated with increased caspase-1 activity, but not IL-1β secretion. Our results define an NLRP3/caspase-1–mediated mechanism of statin-induced insulin resistance in adipose tissue and adipocytes, which may be a contributing factor to statin-induced development of type 2 diabetes. These results warrant scrutiny of insulin sensitivity during statin use and suggest that combination therapies with glyburide, or other inhibitors of the NLRP3 inflammasome, may be effective in preventing the adverse effects of statins.

Is immunity a mechanism contributing to statin-induced diabetes?

“…20 Our first finding corresponded with previous research showing statins increase IL-1b secretion in bone marrow derived macrophages (BMDM's) given adequate priming. 56 Statin-induced IL-1b secretion was dependent on NLRP3 and reversed with (a high dose of) the known inflammasome inhibitor, glyburide.…”

“…Statin-mediated inhibition of HMGCR, decreased mevalonate pathway intermediates and reduced protein prenylation may be a critical link, since addition of GGPP to statin-treated culture has been shown to restore ATP levels and inhibit IL-1b release. 17,20,56,59 However, it is not clear which prenylated protein(s) is/are involved. Three distinct prenyltransferases (Farnesyltransferase, FTase; Geranylgeranyltransferase I and II, GGTase-I and GGTase-II) are responsible for prenylation of an array of proteins including Ras, Rho and Rab family proteins.…”

“…Our data suggests this is worthwhile investigating because we have yet to find a protocol for feeding a statin to a healthy chow-fed mouse that alters glucose control or insulin sensitivity (unpublished), but we found that fluvastatin feeding to ob/ob mice promotes insulin resistance in adipose tissue. 20 Ob/ob mice have several features that could equate to increased priming of the NLRP3 inflammasome, including those related to increased adiposity (endogenous lipids, death of adipose resident cells) and substantial metabolic endotoxemia. 77,78 Hence, it is possible that increased priming of the NLRP3 inflammasome in ob/ob mice promotes statin-induced insulin resistance in the adipose tissue microenvironment.…”

“…13,14 However, statins are not simply anti-inflammatory and a series of findings, including our own, have demonstrated the paradoxical statin-induced increase in IL1b secretion as a result of decreased protein prenylation in immune cells such as macrophages. [15][16][17][18][19][20] …”

“…We found no priming effect of statins alone in macrophages. 20 Cell or tissue culture models are typically primed with bacterial components such as LPS or peptidoglycan before an NLRP3 activating agent is tested. In theory, any stimuli that increases NF-kB-mediated transcription of inflammasome components (and/or pro-IL-1/18) is a potential priming agent for this inflammasome.…”