| First Author | Henriksbo BD | Year | 2019 |
| Journal | Diabetes | Volume | 68 |
| Issue | 7 | Pages | 1441-1448 |
| PubMed ID | 31010959 | Mgi Jnum | J:276949 |
| Mgi Id | MGI:6315743 | Doi | 10.2337/db18-0999 |
| Citation | Henriksbo BD, et al. (2019) Statins Promote Interleukin-1beta-Dependent Adipocyte Insulin Resistance Through Lower Prenylation, Not Cholesterol. Diabetes 68(7):1441-1448 |
| abstractText | Statins lower cholesterol and adverse cardiovascular outcomes, but this drug class increases diabetes risk. Statins are generally anti-inflammatory. However, statins can promote inflammasome-mediated adipose tissue inflammation and insulin resistance through an unidentified immune effector. Statins lower mevalonate pathway intermediates beyond cholesterol, but it is unknown whether lower cholesterol underpins statin-mediated insulin resistance. We sought to define the mevalonate pathway metabolites and immune effectors that propagate statin-induced adipose insulin resistance. We found that LDL cholesterol lowering was dispensable, but statin-induced lowering of isoprenoids required for protein prenylation triggered NLRP3/caspase-1 inflammasome activation and interleukin-1beta (IL-1beta)-dependent insulin resistance in adipose tissue. Multiple statins impaired insulin action at the level of Akt/protein kinase B signaling in mouse adipose tissue. Providing geranylgeranyl isoprenoids or inhibiting caspase-1 prevented statin-induced defects in insulin signaling. Atorvastatin (Lipitor) impaired insulin signaling in adipose tissue from wild-type and IL-18(-/-) mice, but not IL-1beta(-/-) mice. Atorvastatin decreased cell-autonomous insulin-stimulated lipogenesis but did not alter lipolysis or glucose uptake in 3T3-L1 adipocytes. Our results show that statin lowering of prenylation isoprenoids activates caspase-1/IL-1beta inflammasome responses that impair endocrine control of adipocyte lipogenesis. This may allow the targeting of cholesterol-independent statin side effects on adipose lipid handling without compromising the blood lipid/cholesterol-lowering effects of statins. |
