| First Author | Henriksbo BD | Year | 2020 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 319 |
| Issue | 1 | Pages | E110-E116 |
| PubMed ID | 32421368 | Mgi Jnum | J:296835 |
| Mgi Id | MGI:6469119 | Doi | 10.1152/ajpendo.00125.2020 |
| Citation | Henriksbo BD, et al. (2020) Statins activate the NLRP3 inflammasome and impair insulin signaling via p38 and mTOR. Am J Physiol Endocrinol Metab 319(1):E110-E116 |
| abstractText | Statins lower cholesterol and risk of cardiovascular disease. Statins can increase blood glucose and risk of new-onset diabetes. It is unclear why statins can have opposing effects on lipids versus glucose. Statins have cholesterol-independent pleiotropic effects that influence both insulin and glucose control. Statin lowering of isoprenoids required for protein prenylation promotes pancreatic beta-cell dysfunction and adipose tissue insulin resistance. Protein prenylation influences immune function and statin-mediated adipose tissue insulin resistance involves the NLR family pyrin domain-containing 3 (NLRP3) inflammasome and IL-1beta. However, the intracellular cues that statins engage to activate the NLRP3 inflammasome and those responsible for IL-1beta-mediated insulin resistance in adipose tissue have not been identified. We hypothesized that stress kinases or components of the insulin signaling pathway mediated statin-induced insulin resistance. We tested the associations of p38, ERK, JNK, phosphatase, and tensin homolog (PTEN), and mTOR in statin-exposed adipose tissue from WT and IL-1beta(-/-) mice. We found that statins increased phosphorylation of p38 in WT and IL-1beta(-/-) mice. Statin activation of p38 upstream of IL-1beta led to priming of this NLRP3 inflammasome effector in macrophages. We found that mTORC1 inhibition with low doses of rapamycin (2 or 20 nM) lowered macrophage priming of IL-1beta mRNA and secretion of IL-1beta caused by multiple statins. Rapamycin (20 nM) or the rapalog everolimus (20 nM) prevented atorvastatin-induced lowering of insulin-mediated phosphorylation of Akt in mouse adipose tissue. These results position p38 and mTOR as mediators of statin-induced insulin resistance in adipose tissue and highlight rapalogs as candidates to mitigate the insulin resistance and glycemic side effects of statins. |
