SBI-477
目录号 : GC39147SBI-477 is an insulin signaling inhibitor that deactivates the transcription factor MondoA, leading to reduced expression of the insulin pathway suppressors thioredoxin-interacting protein (TXNIP) and arrestin domain-containing 4 (ARRDC4). SBI-477 inhibits triacylglyceride (TAG) synthesis and enhances basal glucose uptake in human skeletal myocytes.
Cas No.:781628-99-7
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SBI-477 is an insulin signaling inhibitor that deactivates the transcription factor MondoA, leading to reduced expression of the insulin pathway suppressors thioredoxin-interacting protein (TXNIP) and arrestin domain-containing 4 (ARRDC4). SBI-477 inhibits triacylglyceride (TAG) synthesis and enhances basal glucose uptake in human skeletal myocytes.
SBI-477, that coordinately inhibits triacylglyceride (TAG) synthesis and enhances basal glucose uptake in human skeletal myocytes, stimulates insulin signaling by deactivating the transcription factor MondoA, leading to reduced expression of the insulin pathway suppressors thioredoxin-interacting protein (TXNIP) and arrestin domain containing 4 (ARRDC4).[1]
[1] Byungyong Ahn, et al. J Clin Invest. 2016 Sep 1;126(9):3567-79.
Cas No. | 781628-99-7 | SDF | |
Canonical SMILES | O=C(NC1=NC(C2=CC=C(OC)C=C2)=CS1)C3=CC=C(OCC(N4CCOCC4)=O)C(OC)=C3 | ||
分子式 | C24H25N3O6S | 分子量 | 483.54 |
溶解度 | DMSO: 65 mg/mL (134.43 mM) | 储存条件 | Store at -20°C |
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MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling
J Clin Invest 2016 Sep 1;126(9):3567-79.PMID:27500491DOI:10.1172/JCI87382.
Intramuscular lipid accumulation is a common manifestation of chronic caloric excess and obesity that is strongly associated with insulin resistance. The mechanistic links between lipid accumulation in myocytes and insulin resistance are not completely understood. In this work, we used a high-throughput chemical biology screen to identify a small-molecule probe, SBI-477, that coordinately inhibited triacylglyceride (TAG) synthesis and enhanced basal glucose uptake in human skeletal myocytes. We then determined that SBI-477 stimulated insulin signaling by deactivating the transcription factor MondoA, leading to reduced expression of the insulin pathway suppressors thioredoxin-interacting protein (TXNIP) and arrestin domain-containing 4 (ARRDC4). Depleting MondoA in myocytes reproduced the effects of SBI-477 on glucose uptake and myocyte lipid accumulation. Furthermore, an analog of SBI-477 suppressed TXNIP expression, reduced muscle and liver TAG levels, enhanced insulin signaling, and improved glucose tolerance in mice fed a high-fat diet. These results identify a key role for MondoA-directed programs in the coordinated control of myocyte lipid balance and insulin signaling and suggest that this pathway may have potential as a therapeutic target for insulin resistance and lipotoxicity.
Single-Nucleotide Polymorphism of the MLX Gene Is Associated With Takayasu Arteritis
Circ Genom Precis Med 2018 Oct;11(10):e002296.PMID:30354298DOI:10.1161/CIRCGEN.118.002296.
Background: Takayasu arteritis (TAK) is an autoimmune systemic arteritis of unknown pathogenesis. Genome-wide association studies revealed that single-nucleotide polymorphisms in the MLX gene encoding the MLX (Max-like protein X) transcription factor are significantly associated with TAK in Japanese patients. MLX single-nucleotide polymorphism rs665268 is a missense mutation causing the Q139R substitution in the DNA-binding site of MLX. Methods: To elucidate the hypothesis that the single-nucleotide polymorphism of the MLX gene plays a critical role in the development of TAK, we conducted clinical and laboratory analyses. Results: We show that rs665268 significantly correlated with the severity of TAK, including the number of arterial lesions and morbidity of aortic regurgitation; the latter may be attributed to the fact that MLX mRNA expression was mostly detected in the aortic valve. Furthermore, the Q139R mutation caused structural changes in MLX, which resulted in enhanced formation of a heterodimer with MondoA, upregulation of TXNIP (thioredoxin-interacting protein) expression, and increase in the activity of the NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome and cellular oxidative stress. Furthermore, autophagy, which negatively regulates inflammasome activation, was suppressed by the Q139R mutation in MLX. The MLX-Q139R mutant significantly induced macrophage proliferation and macrophage-endothelium interaction, which was abolished by the treatment with SBI-477, an inhibitor of MondoA nuclear translocation. Our findings suggest that the Q139R substitution in MLX plays a crucial role in the pathogenesis of TAK. Conclusions: MLX-Q139R mutation plays a crucial role in the pathogenesis of TAK through promoting inflammasome formation.