Statins activate the NLRP3 inflammasome and impair insulin signaling via p38 and mTOR.
Am J Physiol Endocrinol Metab
; 319(1): E110-E116, 2020 07 01.
Article
en En
| MEDLINE
| ID: mdl-32421368
ABSTRACT
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 ß-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-1ß. However, the intracellular cues that statins engage to activate the NLRP3 inflammasome and those responsible for IL-1ß-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-1ß-/- mice. We found that statins increased phosphorylation of p38 in WT and IL-1ß-/- mice. Statin activation of p38 upstream of IL-1ß 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-1ß mRNA and secretion of IL-1ß 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.
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Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Resistencia a la Insulina
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Inhibidores de Hidroximetilglutaril-CoA Reductasas
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Proteínas Quinasas p38 Activadas por Mitógenos
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Inflamasomas
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Serina-Treonina Quinasas TOR
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Atorvastatina
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Proteína con Dominio Pirina 3 de la Familia NLR
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Insulina
Límite:
Animals
Idioma:
En
Revista:
Am J Physiol Endocrinol Metab
Asunto de la revista:
ENDOCRINOLOGIA
/
FISIOLOGIA
/
METABOLISMO
Año:
2020
Tipo del documento:
Article
País de afiliación:
Canadá