Department of Biochemistry and Biomedical Sciences and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow, India.
Diabetes. 2019 Jul;68(7):1441-1448. doi: 10.2337/db18-0999. Epub 2019 Apr 22.
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-1β (IL-1β)-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-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 activates caspase-1/IL-1β 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.
他汀类药物降低胆固醇和心血管不良结局，但这类药物会增加糖尿病风险。他汀类药物通常具有抗炎作用。然而，他汀类药物通过一种未识别的免疫效应物促进炎症小体介导的脂肪组织炎症和胰岛素抵抗。他汀类药物降低了甲羟戊酸途径中间产物，不仅限于胆固醇，但尚不清楚降低胆固醇是否是他汀类药物介导的胰岛素抵抗的基础。我们试图确定促进他汀类药物诱导的脂肪胰岛素抵抗的甲羟戊酸途径代谢物和免疫效应物。我们发现，降低 LDL 胆固醇是不必要的，但他汀类药物诱导的异戊烯基的降低对于蛋白质 prenylation 所需的 isoprenoids 触发 NLRP3/caspase-1 炎症小体激活和白细胞介素-1β（IL-1β）依赖性脂肪组织胰岛素抵抗是必需的。多种他汀类药物在小鼠脂肪组织中损害 Akt/蛋白激酶 B 信号转导水平的胰岛素作用。提供 geranylgeranyl isoprenoids 或抑制 caspase-1 可预防他汀类药物诱导的胰岛素信号转导缺陷。阿托伐他汀（立普妥）在野生型和 IL-18 小鼠的脂肪组织中损害胰岛素信号转导，但在 IL-1β 小鼠中则不会。阿托伐他汀降低了细胞自主的胰岛素刺激的脂肪生成，但在 3T3-L1 脂肪细胞中并没有改变脂肪分解或葡萄糖摄取。我们的结果表明，他汀类药物降低 prenylation isoprenoids 会激活 caspase-1/IL-1β 炎症小体反应，从而损害脂肪细胞脂肪生成的内分泌控制。这可能允许靶向胆固醇非依赖性他汀类药物副作用对脂肪脂质处理，而不影响他汀类药物降低血液脂质/胆固醇的效果。
