Traditional Chinese Medicine Lingguizhugan Decoction Ameliorate HFD-Induced Hepatic-Lipid Deposition in Mice by Inhibiting STING-Mediated Inflammation in Macrophages

Abstract

\n Background: Stimulator of IFN genes (STING) is highly expressed in the livers of non-alcoholic fatty liver disease(NAFLD) patients and HFD induced NAFLD mice model. The STING signaling induced inflammation has been shown to be a critical role in metabolic disorders, such as NAFLD and Type 2 diabetes. Lingguizhugan decoction (LGZG), a Traditional Chinese herbal decoction, has been applied to treat metabolic disorders for many years. However, whether LGZG can alleviate the progression of NAFLD through inhibiting inflammation is not fully understood. This study was to determine the role of STING-mediated inflammation in the HFD- induced hepatic-lipid deposition treated with LGZG.Methods: The anti-inflammatory and anti- hepatic-lipid deposition effects of LGZG in vivo were detected by H&E staining, immunofluorescence and immunochemistry. Mice bone-marrow-derived macrophages (BMDMs) were co-incubated with palmitic acid-induced lipid deposition HepG2 cell model (BMDM+PA-HepG2) and treated with LGZG.STING-specific agonist or blockers respectively to detect whether the activation of STING-mediated pathway is involved in the anti-hepatocyte lipid deposition effect of LGZG. Mitochondrial DNA was detected by real time PCR. The expression of inflammatory cytokines related to STING-TBK1-NF-κB pathway was detected by western blotting and ELISA.Results: LGZG significantly ameliorated HFD induced hepatic steatosis, alleviated insulin resistance (IR) and reduced the oxidative stress. Furthermore, LGZG reduced hepatic mitochondrial damage and mitochondrial DNA release, which corresponded to reducing the expression of STING as well as the the infiltration of STING-positive Kupffer cells in the liver of HFD fed mice. LGZG directly inhibited the activation of STING-TBK1-NF-κB pathway in BMDM induced by DMXAA, LPS, thereby reducing the release of IFNβ and TNFα. Co-incubation LGZG treated BMDM and PA-stimulated HepG2 significantly reduced PA-induced lipid deposition in HepG2 cells by inhibiting STING- mediated signal pathways. Conclusion: This study demonstrates that LGZG can ameliorate HFD-induced hepatic -lipid deposition through inhibiting STING-TBK1-NF-κB pathway in macrophages, which provides novel insight for elucidating the molecular mechanism of LGZG alleviating HFD induced hepatic steatosis.