Editors' ChoiceMetabolic Disease

And the MVP award goes to: Major vault protein

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Science Translational Medicine  08 May 2019:
Vol. 11, Issue 491, eaax4877
DOI: 10.1126/scitranslmed.aax4877

Abstract

MVP functions as an endogenous suppressor of NF-κB and regulates obesity-associated metabolic disease.

Work over the past two decades has shown that over-nutrition activates abnormal immune responses and results in chronic low-grade inflammation in various tissues, which demonstrates a causal relationship between immune and metabolic pathways. Evidence suggests that this low-grade metabolic inflammation contributes to pathogenesis of obesity-associated metabolic diseases, including type 2 diabetes, liver disease, and atherosclerosis. Numerous studies have shown that activation of nuclear factor κΒ (NF-κΒ)−IκΒ kinase pathway is a critical player in metabolic inflammation; however, endogenous regulatory mechanisms that prevent aberrant activation of this pathway are not well studied. Recent work by Ben and colleagues identifies major vault protein (MVP) as a negative regulator of NF-κΒ signaling and suggests that it plays a crucial role in the development of obesity-associated insulin resistance, fatty liver, and atherosclerosis.

Compared with chow-fed lean mice, high-fat diet–fed mice had increased MVP expression in adipose tissue macrophages and peritoneal macrophages. To study the relevance to humans, the authors measured the expression of MVP in the visceral adipose tissue of obese individuals and found substantial up-regulation of MVP in obese human macrophages, suggesting a role for MVP in obesity-induced inflammation. Studies using both whole-body and macrophage-specific Mvp–/– mice revealed that MVP deficiency exacerbated high-fat diet–induced obesity and metabolic inflammation, which correlated with worsening of glucose and insulin tolerance and fatty liver disease. Interestingly, no change in these parameters was observed in MVP-deficient chow-fed lean mice, indicating a specific role of MVP in obesity-associated metabolic alterations. Moreover, MVP was up-regulated in the atherosclerotic plaques of athero-prone ApoE–/– mice, and MVP deficiency resulted in larger lesions which expressed higher proinflammatory cytokines. Mechanistically, the authors found that loss of MVP activated NF-κΒ signaling by enhancing the oligomerization and polyubiquitination of the NF-κΒ regulator, tumor necrosis factor receptor–associated factor 6 (TRAF6).

Understanding the mechanisms that modulate inflammatory responses in obesity may pave the way to new therapeutic strategies. It is important to note that intact inflammatory pathways are essential to maintain tissue homeostasis. Further studies are needed to test whether targeting MVP can be exploited to treat metabolic disorders without altering the host defense system.

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