Nonalcoholic fatty liver disease (NAFLD) is a serious disease. There are no specific drugs for it, in part because of the lack of effective models to aid drug development. However, it has been shown that three-dimensional organoid culture systems can reproduce the organ structure and maintain the gene expression profile of the original tissue. Therefore, we aimed to construct NAFLD models from liver organoids for pharmacological and mechanism studies. We successfully observed morphological changes in normal liver tissue in mouse liver organoids with positive albumin (ALB) expression and potential for differentiation toward hepatocyte-like cells. The mRNA expression of the hepatocyte markers ALB and hepatocyte nuclear factor 4 alpha increased after liver organoid differentiation. We observed free fatty acid (FFA)-induced lipid accumulation in organoids with significant increases in alanine aminotransferase, aspartate aminotransferase, total bilirubin, and triglyceride levels. Moreover, FFA-induced inflammatory cytokines (interleukin-6, tumor necrosis factor-α, and nitric oxide) and fibrosis indicators (collagen type I α1 and laminin α1) were also increased. In addition, RNA sequencing results showed that the expression of key genes [nucleotide oligomerization domain-like receptor (NLR) family apoptosis inhibitory protein, interferon regulatory factor (IRF) 3, and IRF7] involved in NAFLD metabolic abnormalities and insulin resistance in the NLR signaling pathway was altered after FFA induction of the liver organoids. Finally, we found that JC2-11 and lanifibranor limited the FFA-induced increase in oil-red lipid droplets, liver damage, inflammation, and liver fibrosis. In conclusion, tissue structure, gene expression, and the response of mouse liver organoids to drugs can partially mimic in vivo liver tissue. Liver organoids can successfully construct NAFLD models for drug discovery research.

2024-06-01·Immunity, Inflammation and Disease

AIM2 inflammasome regulated by the IFN‐γ/JAK2/STAT1 pathway promotes activation and pyroptosis of monocytes in Coronary Artery Disease

Article

作者: Shen, Changxin ; Zhang, Xiaokang ; Cheng, Yating ; Wang, Chen ; Zhao, Yue ; Zheng, Fang ; Liang, Bin ; Sheng, Shuyang ; Jin, Bingyu

AbstractBackgroundNumerous studies have demonstrated that Absent in Melanoma 2 (AIM2) is upregulated in aortic plaques, especially in Vascular Smooth Muscle Cells in Coronary Artery Disease (CAD), and is related to inflammasome‐induced inflammation. However, the underlying mechanism of this phenomenon and the role of AIM2 in atherosclerosis remained unclear.MethodsThis study enrolled 133 CAD patients and 123 controls. We isolated Peripheral Blood Leukocytes (PBLs) and the mRNA expression of AIM2 inflammasome and its downstream genes (ASC, Caspase‐1, IL‐1β, and IL‐18) were detected by real‐time quantitative PCR (qPCR). We assessed correlations between AIM2 expressions and clinical characteristics by multiple linear regression and spearman's correlation. The THP‐1 cells cultured in poly(dA:dT), A151, interferon‐gamma (IFN‐γ), AG490, or JC2‐11. And then the mRNA and protein levels of AIM2, ASC, Caspase‐1, IL‐1β, IL‐18, GSDMD, and STAT1 were analyzed by qPCR and Western blot analysis, respectively. The migration and adhesive capacity of THP‐1 cells was assessed using an inverted microscope and an inverted fluorescence microscope, respectively.ResultsIn this study, we found that expressions of components of AIM2 inflammasome and its downstream genes (ASC, Caspase‐1, IL‐1β, and IL‐18), were all increased in PBLs of CAD patients, which indicated the inflammasome activation. AIM2 inflammasome activation further induced pyroptosis, and stimulated migration and adhesion in monocyte cell lines, which was regulated by IFN‐γ probably through JAK2/STAT1 pathway. In addition, AIM2 expressions were positively correlated with systemic inflammatory indicators as an independent risk factor for CAD.ConclusionsIn conclusion, increased AIM2 expression, induced by the IFN‐γ/JAK2/STAT1 signal, orientates monocytes to inflammatory status or even pyroptosis through AIM2 inflammasome activation, which is involved in the development of CAD.

100 项与 JC2-11 相关的药物交易

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