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J Lipid Res. 2016 Jan;57(1):66-76. doi: 10.1194/jlr.M062828. Epub 2015 Dec 1.

Suppression of NLRP3 inflammasome by γ-tocotrienol ameliorates type 2 diabetes.

Author information

1
Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583.
2
Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583 schung4@unl.edu.

Abstract

The Nod-like receptor 3 (NLRP3) inflammasome is an intracellular sensor that sets off the innate immune system in response to microbial-derived and endogenous metabolic danger signals. We previously reported that γ-tocotrienol (γT3) attenuated adipose tissue inflammation and insulin resistance in diet-induced obesity, but the underlying mechanism remained elusive. Here, we investigated the effects of γT3 on NLRP3 inflammasome activation and attendant consequences on type 2 diabetes. γT3 repressed inflammasome activation, caspase-1 cleavage, and interleukin (IL) 1β secretion in murine macrophages, implicating the inhibition of NLRP3 inflammasome in the anti-inflammatory and antipyroptotic properties of γT3. Furthermore, supplementation of leptin-receptor KO mice with γT3 attenuated immune cell infiltration into adipose tissue, decreased circulating IL-18 levels, preserved pancreatic β-cells, and improved insulin sensitivity. Mechanistically, γT3 regulated the NLRP3 inflammasome via a two-pronged mechanism: 1) the induction of A20/TNF-α interacting protein 3 leading to the inhibition of the TNF receptor-associated factor 6/nuclear factor κB pathway and 2) the activation of AMP-activated protein kinase/autophagy axis leading to the attenuation of caspase-1 cleavage. Collectively, we demonstrated, for the first time, that γT3 inhibits the NLRP3 inflammasome thereby delaying the progression of type 2 diabetes. This study also provides an insight into the novel therapeutic values of γT3 for treating NLRP3 inflammasome-associated chronic diseases.

KEYWORDS:

A20; NOD-like receptor protein 3; caspase 1; diet and dietary lipids; inflammation; insulin signaling; obesity; vitamin E

PMID:
26628639
PMCID:
PMC4689338
DOI:
10.1194/jlr.M062828
[Indexed for MEDLINE]
Free PMC Article

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