Overexpression of NAG-1/GDF15 prevents hepatic steatosis through inhibiting oxidative stress-mediated dsDNA release and AIM2 inflammasome activation

Wang, Ying; Chen, Chaojie; Chen, Jiajun; Sang, Tingting; He, Peng; Lin, Xiaojian; Zhao, Qian; Chen, Shengjia; Eling, Thomas E.; Wang, Xingya

doi:10.1016/j.redox.2022.102322

Cited by 56 publications

(28 citation statements)

References 131 publications

(177 reference statements)

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“…Ying Wang et al. reported that overexpression of NSAID‐activated gene‐1 (NAG‐1), or growth differentiation factor‐15 (GDF15) in transgenic (Tg) mice significantly alleviated high‐fat‐diet‐induced obesity and hepatic steatosis 35 . However, we demonstrated a significantly increased risk of NAFLD risk in RA patients treated with NSAIDs in our study.…”

Section: Discussioncontrasting

confidence: 76%

Antirheumatic drugs and the risk of nonalcoholic fatty liver disease in patients with rheumatoid arthritis: A nationwide, population‐based cohort study

Meng,

Chen,

Chen

et al. 2023

Int J of Rheum Dis

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ObjectivesTo assess the association between antirheumatic drugs and of the risk of nonalcoholic fatty liver disease (NAFLD) in a nationwide rheumatoid arthritis (RA) cohort.MethodsUsing claim data from the 2000–2020 National Health Insurance Research Database, we identified 21 457 incident patients with RA from 2002 to 2020 without prior liver diseases. A time‐varying multivariable Cox regression model was applied to estimate for the association of NAFLD with the use of antirheumatic drugs after adjusting potential confounders, show as adjusted hazard ratios (aHRs) with 95% confidence interval (CIs). Subgroup analyses were conducted based on age‐, sex‐, and obesity‐related comorbidities.ResultsMultivariable time‐dependent Cox regression analyses showed that defined daily dose (DDD) of NSAID (aHR, 1.03; 95% CI: 1.02–1.05) and prednisolone equivalent dose >5 mg/day (aHR, 2.39; 95% CI: 1.85–3.09) were risk factors of NAFLD in patients with RA, while prednisolone equivalent dose ≤5 mg/day (aHR of 0.53; 95% CI: 0.40–0.71) and HCQ use (aHR of 0.75; 95% CI: 0.60–0.93) were associated with a decreased risk of NAFLD. In addition, a history of hospitalizations, number of outpatient visits, age, male, and leflunomide use were associated with the development of NAFLD in some subgroups.ConclusionThis study reveals that NSAID use and prednisolone equivalent dose >5 mg/day were associated with an increased risk of NAFLD in patients with RA, while the use of HCQ and prednisolone equivalent dose ≤5 mg/day decreased the risk of NAFLD.

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Section: Discussioncontrasting

confidence: 76%

Antirheumatic drugs and the risk of nonalcoholic fatty liver disease in patients with rheumatoid arthritis: A nationwide, population‐based cohort study

Meng,

Chen,

Chen

et al. 2023

Int J of Rheum Dis

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“…A previous study reported that Con A treatment increased liver‐specific ROS, leading to damage associated with oxidative stress in the liver 54 . Oxidative stress plays an important role in liver disease development 55,56 . Namely, MDA is a marker of lipid peroxidation in membranes, and MDA levels in the liver were previously reported to increase with Con A treatment 57 .…”

Section: Discussionmentioning

confidence: 97%

“…54 Oxidative stress plays an important role in liver disease development. 55,56 Namely, MDA is a marker of lipid peroxidation in membranes, and MDA levels in the liver were previously reported to increase with Con A treatment. 57 Accordingly, MDA levels in liver tissues were measured in the present study, and reduced MDA levels were found in the IL-28A-deficiency group compared with those in the Con A group.…”

Section: Discussionmentioning

confidence: 99%

Interleukin 28A aggravates Con A‐induced acute liver injury by promoting the recruitment of M1 macrophages

Zhang,

Cheng,

Zhang

et al. 2024

The FASEB Journal

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Immune‐mediated acute hepatic injury is characterized by the destruction of a large number of hepatocytes and severe liver function damage. Interleukin‐28A (IL‐28A), a member of the IL‐10 family, is notable for its antiviral properties. However, despite advances in our understanding of IL‐28A, its role in immune‐mediated acute injury remains unclear. The present study investigated the role of IL‐28A in concanavalin A (Con A)‐induced acute immune liver injury. After Con A injection in mice, IL‐28A level significantly increased. IL‐28A deficiency was found to protect mice from acute liver injury, prolong survival time, and reduce serum aspartate aminotransferase and alanine aminotransferase levels. In contrast, recombinant IL‐28A aggravated liver injury in mice. The proportion of activated M1 macrophages was significantly lower in the IL‐28A‐deficiency group than in the wild‐type mouse group. In adoptive transfer experiments, M1 macrophages from WT could exacerbate mice acute liver injury symptoms in the IL‐28A deficiency group. Furthermore, the expression of proinflammatory cytokines, including tumor necrosis factor‐α (TNF‐α), IL‐12, IL‐6, and IL‐1β, by M1 macrophages decreased significantly in the IL‐28A‐deficiency group. Western blotting demonstrated that IL‐28A deficiency could limit M1 macrophage polarization by modulating the nuclear factor (NF)‐κB, mitogen‐activated protein kinase (MAPK), and interferon regulatory factor (IRF) signaling pathways. In summary, IL‐28A deletion plays an important protective role in the Con A‐induced acute liver injury model and IL‐28A deficiency inhibits the activation of M1 macrophages by inhibiting the NF‐κB, MAPK, and IRF signaling pathways. These results provide a potential new target for the treatment of immune‐related hepatic injury.

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“…Inhibition of AIM2 expression or transfection of AIM2 siRNA can significantly inhibit the proliferation and inflammatory behavior of FLS ( 175 ). ROS is a key factor leading to mtDNA leakage, and inhibition of oxidative stress contributes to reduction of mitochondrial damage, release of dsDNA, and activation of AIM2 ( 176 ). Additionally, ROS assisted in the process of AIM2 activation during bacterial infection ( 177 ).…”

Section: Role Of Ros and Mitochondrial Damage In Ra Inflammationmentioning

confidence: 99%

Role of reactive oxygen species and mitochondrial damage in rheumatoid arthritis and targeted drugs

et al. 2023

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Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation, pannus formation, and bone and cartilage damage. It has a high disability rate. The hypoxic microenvironment of RA joints can cause reactive oxygen species (ROS) accumulation and mitochondrial damage, which not only affect the metabolic processes of immune cells and pathological changes in fibroblastic synovial cells but also upregulate the expression of several inflammatory pathways, ultimately promoting inflammation. Additionally, ROS and mitochondrial damage are involved in angiogenesis and bone destruction, thereby accelerating RA progression. In this review, we highlighted the effects of ROS accumulation and mitochondrial damage on inflammatory response, angiogenesis, bone and cartilage damage in RA. Additionally, we summarized therapies that target ROS or mitochondria to relieve RA symptoms and discuss the gaps in research and existing controversies, hoping to provide new ideas for research in this area and insights for targeted drug development in RA.

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Overexpression of NAG-1/GDF15 prevents hepatic steatosis through inhibiting oxidative stress-mediated dsDNA release and AIM2 inflammasome activation

Cited by 56 publications

References 131 publications

Antirheumatic drugs and the risk of nonalcoholic fatty liver disease in patients with rheumatoid arthritis: A nationwide, population‐based cohort study

Antirheumatic drugs and the risk of nonalcoholic fatty liver disease in patients with rheumatoid arthritis: A nationwide, population‐based cohort study

Interleukin 28A aggravates Con A‐induced acute liver injury by promoting the recruitment of M1 macrophages

Role of reactive oxygen species and mitochondrial damage in rheumatoid arthritis and targeted drugs

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