Effects of Statins on Adipose Tissue Inflammation: Their Inhibitory Effect on MyD88-Independent IRF3/IFN- Pathway in Macrophages

Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 06/2008; 28(5):871-7. DOI: 10.1161/ATVBAHA.107.160663
Source: PubMed


Macrophage-mediated chronic inflammation of adipose tissue is causally linked to insulin resistance in obesity. The beneficial effects of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase inhibitors (statins) on glucose metabolism have been suggested, but the effects of these agents on adipose tissue inflammation are unclear. The aim of the present study is to define the effects of statins on adipose tissue inflammation and macrophages.
Pravastatin or pitavastatin treatment of obese mice attenuated an increase in mRNA expressions of proinflammatory genes, including MCP1 and IL6, in adipose tissue. The supernatant of TLR4-stimulated RAW264 macrophages strongly induced the expression of these genes in 3T3-L1 adipocytes, which was inhibited by pretreatment of macrophages with either statin. Statins inhibited TLR4-mediated activation of interferon (IFN) regulatory factor (IRF)3 by either lipopolysaccharide (LPS) or palmitic acid, resulting in suppression of IFN-beta expression, but not that of NF-kappaB or JNK. Moreover, statins strongly downregulated TLR3-mediated gene expressions by poly(I:C), but not TLR2-stimulation by zymosan A. Neutralization of IFN-beta attenuated proinflammatory activities of the macrophage supernatant.
Statins partially attenuated the development of adipose tissue inflammation in obese mice, which might be associated with an inhibitory effect of statins on TLR4-triggered expression of IFN-beta via MyD88-independent signaling pathway in macrophages.

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    • "Other receptors of the innate immune system such as Nod-like receptors are also implicated in obesity and high saturated fatassociated adipose inflammation (Schertzer et al., 2011). Conversely, there is evidence that adipose tissue inflammation can be reduced without changing adipose mass (Abe et al., 2008; DeFuria et al., 2009). This is also consistent with our recent findings that EPA reverses high fat-induced metabolic disorders and adipose inflammation, in the absence of changes in body weight or fat mass (Kalupahana et al., 2010, 2011a). "
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    ABSTRACT: Obesity is a major public health problem in the United States and worldwide. Further, obesity is causally linked to the pathogenesis of insulin resistance, metabolic syndrome and type-2 diabetes (T2D). A chronic low-grade inflammation occurring in adipose tissue is at least in part responsible for the obesity-induced insulin resistance. This adipose tissue inflammation is characterized by changes in immune cell populations giving rise to altered adipo/cytokine profiles, which in turn induces skeletal muscle and hepatic insulin resistance. Detailed molecular mechanisms of insulin resistance, adipose tissue inflammation and the implications of these findings on therapeutic strategies are discussed in this review.
    Molecular Aspects of Medicine 02/2012; 33(1):26-34. DOI:10.1016/j.mam.2011.10.011 · 10.24 Impact Factor
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    • "Statins might have a various direct effects on adipose tissue function by inhibiting Toll-like receptor-4 (TLR4) triggered expression of IFN-γ in macrophages, which are abundant in adipose tissue, and through increasing PPAR- γ expression[125,126]. Besides direct effects on adipose tissue, statins are also capable of reducing inflammation in general as measured by reduced plasma CRP levels[127]. "
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    • "The chronic inflammation of adipose tissue caused by obesity is attracting attention as a possible mechanism of inducing such vascular diseases [2]. While some agents such as thiazolidinediones (TZDs) and statins have been reported to reduce this inflammation, a treatment directly targeting the adipose inflammation has yet been established [3] [4]. LOX-1 is a scavenger receptor [5] and is predominantly expressed by endothelial cells in early foci of atherosclerosis [6]. "
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