PGRN exerts inflammatory effects via SIRT1-NF-κB in adipose insulin resistance.
JOURNAL OF MOLECULAR ENDOCRINOLOGY(2020)
摘要
Progranulin (PGRN), a multifunctional protein implicated in embryonic development and immune response, was recently introduced as a novel marker of chronic inflammation related with insulin resistance in obesity and type 2 diabetes mellitus. However, the potential mechanisms of PGRN on insulin signaling pathways are poorly understood. In this study, PGRN mediated the chemotaxis of RAW264.7, impaired insulin action and stimulated production of inflammatory factors in adipocytes, which was accompanied by increased c-Jun N-terminal kinase (JNK) activation and serine phosphorylation of insulin receptor substrate-1. PGRN knockdown partially led to an increase in insulin action as well as a decrease in the JNK activation and extracel lular signal-regulated kinase phosphorylation in cells exposed to tumor-necrosis factor-alpha (TNF-alpha). Meanwhile, PGRN treatment resulted in an elevation of transcription factor nuclear factor kappa B (NF-kappa B) nuclear translocation and acetylation, and increased Il-1b, Il6, Tnf-alpha expression, whereas NF-kappa B inhibition reversed PGRN-induced insulin action impairment and inflammatory gene expression. Finally, we showed that sirtuin 1 (SIRT1) expression was downregulated by PGRN treatment, whereas SIRT1 overexpression improved PGRN-induced insulin resistance, NF-kappa B activation, and inflammatory gene expression. Our results suggest that PGRN regulates adipose tissue inflammation possibly by controlling the gain of proinflammatory transcription in a SIRT1-NF-kappa B dependent manner in response to inducers such as fatty acids and endoplasmic reticulum stress.
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关键词
PGRN,inflammation,insulin resistance,SIRT1
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