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STING-mediated inflammation in Kupffer cells contributes to progression of nonalcoholic steatohepatitis
Yongsheng Yu, … , Yuefan Zhang, Xianxian Zhao
Yongsheng Yu, … , Yuefan Zhang, Xianxian Zhao
Published December 18, 2018
Citation Information: J Clin Invest. 2019;129(2):546-555. https://doi.org/10.1172/JCI121842.
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Research Article Hepatology

STING-mediated inflammation in Kupffer cells contributes to progression of nonalcoholic steatohepatitis

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Abstract

Innate immune activation contributes to the transition from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH). Stimulator of IFN genes (STING, also referred to Tmem173) is a universal receptor that recognizes released DNA and triggers innate immune activation. In this work, we investigated the role of STING in the progression of NASH in mice. Both methionine- and choline-deficient diet (MCD) and high-fat diet (HFD) were used to induce NASH in mice. Strikingly, STING deficiency attenuated steatosis, fibrosis, and inflammation in livers in both murine models of NASH. Additionally, STING deficiency increased fasting glucose levels in mice independently of insulin, but mitigated HFD-induced insulin resistance and weight gain and reduced levels of cholesterol, triglycerides, and LDL in serum; it also enhanced levels of HDL. The mitochondrial DNA (mtDNA) from hepatocytes of HFD-fed mice induced TNF-α and IL-6 expression in cultured Kupffer cells (KCs), which was attenuated by STING deficiency or pretreatment with BAY11-7082 (an NF-κB inhibitor). Finally, chronic exposure to 5,6-dimethylxanthenone-4-acetic acid (DMXAA, a STING agonist) led to hepatic steatosis and inflammation in WT mice, but not in STING-deficient mice. We proposed that STING functions as an mtDNA sensor in the KCs of liver under lipid overload and induces NF-κB–dependent inflammation in NASH.

Authors

Yongsheng Yu, Yu Liu, Weishuai An, Jingwen Song, Yuefan Zhang, Xianxian Zhao

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Figure 1

Deficiency of STING attenuated MCD-induced hepatic steatosis and fibrosis in mice.

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Deficiency of STING attenuated MCD-induced hepatic steatosis and fibrosi...
WT or STING-deficient mice (Tmem173gt) were exposed to MCD for 8 weeks to induce NASH. Paraffin-embedded liver sections were stained with H&E (A) or Masson-trichrome (B), and hepatic histological scores and fibrosis area were calculated. Scale bars: 200 μm. Graphs showed levels of cholesterol (C), triglycerides (D), and hydroxyproline (E) in livers and levels of ALT (F) and AST (G) in serum. n = 9 in each group. Values are shown as mean ± SD. *P < 0.05 versus WT mice fed with control diet; #P < 0.05 versus WT mice fed with MCD. Statistical significance was determined using 1-way ANOVA followed by Tukey-Kramer multiple comparisons test.
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