Statins Promote IL-1β-Dependent Adipocyte Insulin Resistance via Lower Prenylation not Cholesterol Academic Article uri icon

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abstract

  • 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 if 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 IL-1β-dependent insulin resistance in adipose tissue. Multiple statins impaired insulin action at the level of Akt/PKB signaling in mouse adipose tissue. Providing geranylgeranyl isoprenoids or inhibiting caspase-1 prevented statin-induced defects in insulin signaling. Atorvastatin (LipitorTM) impaired insulin signaling in adipose tissue from WT and IL-18-/- mice, but not IL-1β-/- 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 activate caspase-1/IL-1β inflammasome responses that impair endocrine control of adipocyte lipogenesis. This may allow targeting of cholesterol-independent statin side-effects on adipose lipid handling without compromising the blood lipid/cholesterol lowering effects of statins.

authors

  • Henriksbo, Brandyn D
  • Tamrakar, Akhilesh K
  • Xu, Joshua
  • Duggan, Brittany M
  • Cavallari, Joseph F
  • Phulka, Jobanjit
  • Stampfli, Martin R
  • Ashkar, Ali A
  • Schertzer, Jonathan

publication date

  • April 22, 2019