The STING-IRF3 pathway is involved in lipotoxic injury of pancreatic β cells in type 2 diabetes

Hu, Hai-Yang; Qiao, Jingting; Liu, F.Q.; Wang, J.B.; Sha, S.; He, Qin; Cui, Chen; Song, Jie; Zang, Nan; Wang, L.S.; Sun, Zheng; Chen, L.; Hou, Xinguo

doi:10.1016/j.mce.2020.110890

Cited by 48 publications

(44 citation statements)

References 46 publications

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“…An incremented concentration of 2000 µM did not mediate higher toxicity [46]. A 15-70% diminished insulin secretion was induced by a short-or medium-term treatment (up to 72 h) with 400 or 500 µM FFA [47,48]. Exposure to 100 µM for several weeks led to a 20% decrease [49].…”

Section: Factors Influencing Lipotoxic Outcomes In Tissue Culturementioning

confidence: 82%

“…Damaged DNA can be recognized by stimulator of interferon genes (STING), increasing inflammation and apoptosis. The STING pathway is enhanced under lipotoxic conditions and activates interferon regulatory factor 3 [47]. It has been shown that the presence of ceramides is crucial for the induction of apoptosis.…”

Section: Ceramides Increase Oxidative Stress Through Inducible Nitricmentioning

confidence: 99%

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Lipotoxic Impairment of Mitochondrial Function in β-Cells: A Review

2021

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Lipotoxicity is a major contributor to type 2 diabetes mainly promoting mitochondrial dysfunction. Lipotoxic stress is mediated by elevated levels of free fatty acids through various mechanisms and pathways. Impaired peroxisome proliferator-activated receptor (PPAR) signaling, enhanced oxidative stress levels, and uncoupling of the respiratory chain result in ATP deficiency, while β-cell viability can be severely impaired by lipotoxic modulation of PI3K/Akt and mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) pathways. However, fatty acids are physiologically required for an unimpaired β-cell function. Thus, preparation, concentration, and treatment duration determine whether the outcome is beneficial or detrimental when fatty acids are employed in experimental setups. Further, ageing is a crucial contributor to β-cell decay. Cellular senescence is connected to loss of function in β-cells and can further be promoted by lipotoxicity. The potential benefit of nutrients has been broadly investigated, and particularly polyphenols were shown to be protective against both lipotoxicity and cellular senescence, maintaining the physiology of β-cells. Positive effects on blood glucose regulation, mitigation of oxidative stress by radical scavenging properties or regulation of antioxidative enzymes, and modulation of apoptotic factors were reported. This review summarizes the significance of lipotoxicity and cellular senescence for mitochondrial dysfunction in the pancreatic β-cell and outlines potential beneficial effects of plantbased nutrients by the example of polyphenols.

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Section: Factors Influencing Lipotoxic Outcomes In Tissue Culturementioning

confidence: 82%

Section: Ceramides Increase Oxidative Stress Through Inducible Nitricmentioning

confidence: 99%

Lipotoxic Impairment of Mitochondrial Function in β-Cells: A Review

2021

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“…In this setting, STING or cGAS deficiency improved post-MI survival (110). STING activity may attenuate type I diabetes, but exacerbate type II diabetes and the associated metabolic syndrome (97,111,112). The dual positive and negative effects of STING on health mandate caution in modulating STING activity therapeutically.…”

Section: Sting In the "Sterile" Pathology Of Disease Statesmentioning

confidence: 99%

STING, the Endoplasmic Reticulum, and Mitochondria: Is Three a Crowd or a Conversation?

Smith

2021

Front. Immunol.

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The anti-viral pattern recognition receptor STING and its partnering cytosolic DNA sensor cGAS have been increasingly recognized to respond to self DNA in multiple pathologic settings including cancer and autoimmune disease. Endogenous DNA sources that trigger STING include damaged nuclear DNA in micronuclei and mitochondrial DNA (mtDNA). STING resides in the endoplasmic reticulum (ER), and particularly in the ER-mitochondria associated membranes. This unique location renders STING well poised to respond to intracellular organelle stress. Whereas the pathways linking mtDNA and STING have been addressed recently, the mechanisms governing ER stress and STING interaction remain more opaque. The ER and mitochondria share a close anatomic and functional relationship, with mutual production of, and inter-organelle communication via calcium and reactive oxygen species (ROS). This interdependent relationship has potential to both generate the essential ligands for STING activation and to regulate its activity. Herein, we review the interactions between STING and mitochondria, STING and ER, ER and mitochondria (vis-à-vis calcium and ROS), and the evidence for 3-way communication.

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“…The STING signaling has been shown to be a critical role in metabolic disorders, antitumor immunity, infectious and in ammatory diseases through the recognition of bacterial DNA or self DNA [10]. When abnormal double-stranded DNA (such as bacterial, viral DNA, or DNA released by damaged mitochondria, mtDNA) is swallowed by macrophages into the cytoplasm, cyclic guanosine phosphate and adenosine phosphate are activated to form cyclic guanosine phosphate-adenosine phosphate (cGAMP) [11]. STING on the endoplasmic reticulum will be recognized and binded to cGAMP and then activated [11].…”

Section: Introductionmentioning

confidence: 99%

“…STING on the endoplasmic reticulum will be recognized and binded to cGAMP and then activated [11]. The activation of STING pathway simultaneously triggers TANK-binding kinase 1 (TBK1), which induces the phosphorylation of both interferon regulatory factor 3 (IRF3) [11] and NF-κB pathway [12], subsequently increasing the expression of type I interferon (IFN) and TNF-α [11]. STINGmediated signaling pathways play a key role in both liver macrophage-induced in ammation and IRinduced glucose as well as lipid metabolism disorders [13,14].…”

Section: Introductionmentioning

confidence: 99%

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

Cao

Ruan

et al. 2021

Preprint

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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.

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The STING-IRF3 pathway is involved in lipotoxic injury of pancreatic β cells in type 2 diabetes

Cited by 48 publications

References 46 publications

Lipotoxic Impairment of Mitochondrial Function in β-Cells: A Review

Lipotoxic Impairment of Mitochondrial Function in β-Cells: A Review

STING, the Endoplasmic Reticulum, and Mitochondria: Is Three a Crowd or a Conversation?

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

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