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http://hdl.handle.net/11375/24912
Title: | The NLRP3 inflammasome is involved in statin-induced insulin resistance |
Authors: | Henriksbo, Brandyn |
Advisor: | Schertzer, Jonathan |
Department: | Biochemistry and Biomedical Sciences |
Keywords: | Statin;NLRP3 |
Publication Date: | 2019 |
Abstract: | Statins are one of the most widely prescribed drug classes because they lower circulating low density lipoprotein-cholesterol (LDL) and reduce the risk of cardiovascular events. Statin-mediated inhibition of HMG-CoA reductase also lowers substrates required for protein prenylation. This cholesterol-independent effect of statins can alter immune function. Lower protein prenylation can increase IL-1β. This pro-inflammatory cytokine can promote insulin resistance, which may be a factor in the recent evidence linking statins to increased incidence of diabetes. IL-1β is unique compared to most cytokines because it can be regulated by the NLRP3 inflammasome. In this thesis, we discovered that statins promote NLRP3-dependent insulin resistance in adipose tissue. We next hypothesized that statin-induced lowering of protein prenylation activated the NLRP3/Caspase-1 inflammasome, which would cause IL-1β-dependent insulin resistance in adipose tissue. We showed that atorvastatin impaired insulin signalling in adipose tissue from WT, but not IL-1β-/- mice. Treatment with a caspase-1 inhibitor prevented atorvastatin-inhibition of insulin signalling. The isoprenoid, Geranylgeranyl pyrophosphate (GGPP) also prevented atorvastatin-induced defects in insulin signalling. Interestingly, atorvastatin- inhibition of insulin action was associated with decreased insulin-stimulated lipogenesis in both white adipose tissue and 3T3-L1 adipocytes. The findings in this thesis suggest a statin-induced reduction in isoprenoids, required for protein prenylation production, impairs insulin action via IL-1β derived from activation of NLRP3/Caspase-1 inflammasome in adipose tissue. |
URI: | http://hdl.handle.net/11375/24912 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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henriksbo_brandyn_d_201909_phd.pdf | 5.93 MB | Adobe PDF | View/Open |
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