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. / Thesis / Doctor of Philosophy (PhD) / Statins are one of the most widely prescribed drugs and used in the treatment of cardiovascular disease. Statins lower LDL often called bad cholesterol. However, some patients experience side effects such as higher blood glucose and increased risk of type 2 diabetes. Type 2 diabetes is generally preceded by insulin resistance and this period of “prediabetes” is reversible. Inflammation is one factor involved in insulin resistance and in the development of type 2 diabetes. In this thesis, we discover that statins activate an inflammatory response known as the NLRP3 inflammasome, which leads to insulin resistance, particularly in fat tissue. Activation of this inflammasome by a statin, did not require lower cholesterol, but increased the inflammatory cytokine IL-1b, which was the key factor leading to insulin resistance in fat tissue. Inhibition of the NLRP3 inflammasome or IL-1b may prevent insulin resistance and risk of type 2 diabetes in people taking statins.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/24912 |
| Date | January 2019 |
| Creators | Henriksbo, Brandyn |
| Contributors | Schertzer, Jonathan, Biochemistry and Biomedical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
Page generated in 0.0015 seconds