Interferon regulatory factor 3 constrains IKKβ/NF-κB signaling to alleviate hepatic steatosis and insulin resistance

Abstract

Obesity and related metabolic diseases associated with chronic low-grade inflammation greatly compromise human health. Previous observations on the roles of interferon regulatory factors (IRFs) in the regulation of metabolism prompted investigation of the involvement of a key family member, IRF3, in metabolic disorders. IRF3 expression in the liver is decreased in animals with diet-induced and genetic obesity. The global knockout (KO) of IRF3 significantly promotes chronic high-fat diet (HFD)-induced hepatic insulin resistance and steatosis; in contrast, adenoviral-mediated hepatic IRF3 overexpression preserves glucose and lipid homeostasis. Furthermore, systemic and hepatic inflammation, which is increased in IRF3 KO mice, is attenuated by the overexpression of hepatic IRF3. Importantly, inhibitor of nuclear factor kappa B kinase beta subunit / nuclear factor kappa B (IKKb/NF-jB) signaling is repressed by IRF3, and hepatic overexpression of the inhibitor of jB-a (IjBa) reverses HFD-induced insulin resistance and steatosis in IRF3 KO mice. Mechanistically, IRF3 interacts with the kinase domain of IKKb in the cytoplasm and inhibits its downstream signaling. Moreover, deletion of the region of IRF3 responsible for the IRF3/IKKb interaction inhibits the capacity of IRF3 to preserve glucose and lipid homeostasis. Conclusion: IRF3 interacts with IKKb in the cytoplasm to inhibit IKKb/NF-jB signaling, thus alleviating hepatic inflammation, insulin resistance, and hepatic steatosis. (HEPATOLOGY 2014;59:870-885) M etabolic diseases, including obesity, type 2 diabetes (T2D), and nonalcoholic fatty liver disease (NAFLD), currently threaten human lives due to continued urbanization and population aging.1 Evidence from both clinical and basic research substantiates the notion that inflammation underlies the etiology of obesity-related metabolic disorders.

Ablation of Interferon Regulatory Factor 3 Protects Against Atherosclerosis in Apolipoprotein E–Deficient Mice

“…In fact, IRF3 exerts distinct functions in different tissues and cell types via specific mechanisms. For example, IRF3 deficiency in cases of overnutrition aggravates hepatic steatosis and insulin resistance through the IKKβ/NF-κB (IKK-beta/nuclear factor-kappa B) signaling pathway in hepatocytes, 27 whereas our present study did not find any significant differences in the metabolic lipid profiles between IRF3 −/− ApoE −/− mice and ApoE −/− mice. The pressure overload-induced upregulation of IRF3 in cardiomyocytes attenuates the development of cardiac hypertrophy and heart failure via an interaction with ERK2 (extracellular regulated protein kinase 2) that inhibited the activation of ERK1/2 signaling.…”

“…20 In addition, IRF3 induces proatherosclerotic gene expression, including that of RANTES, Ccl5, and Cxcl10, [21][22][23] and affects endothelial cell proliferation. 24 Recently, our group has clarified that IRF3 contributes to cerebral ischemic injury, 25 neointima formation, 26 hepatic steatosis, 27 and cardiac hypertrophy. 28 However, the specific role of IRF3 in the development of atherosclerosis is unclear.…”

Interferon Regulatory Factor Signalings in Cardiometabolic Diseases

“…8 Most recently, our research group found that the mRNA and protein expressions of IRF3 were significantly reduced in the liver of ob/ob mice that were fed normal chow and of C57BL/6J mice that were subjected to HFD administration for 26 weeks. 117 Intriguingly, in white adipose tissue, the expression of IRF3 was upregulated in HFDtreated mice. 118 The alteration of IRF3 expression suggested the potential participation of IRF3 in both spontaneous and inducible obesity.…”

“…The ameliorating effects of IRF3 on abnormal lipid and insulin metabolism were validated by the observations that IRF3 overexpression dramatically decreased the HFD-induced dysfunction of insulin sensitivity and lipid homeostasis, and that IRF3-KO mice showed accelerated and exacerbated adiposity, hepatic steatosis, and insulin resistance compared with wild-type (WT) controls. 117 The protective effect of IRF3 on metabolic disorder is closely associated with its capacity on inflammatory inhibition. The infiltration of macrophages in the white adipose tissue of IRF3-KO mice was much higher than that of WT controls.…”

“…21,22 Applying multiple biological approaches, the interaction between the IAD of IRF3 and the N-terminal domain of IKKβ has been identified to be largely responsible for the metabolic counterbalance property of IRF3. 117 A recent pharmacological study indicated that the downregulation of IRF3 in adipose tissue is involved in the antiobesity effects of resveratrol in HFD-stimulated mice, 119 suggesting a promising strategy of targeting IRF3 for the treatment of metabolic diseases.…”