固醇调节元件结合蛋白（SREBPs）是调控细胞内胆固醇和脂肪酸合成的核心转录因子家族，其活性异常与肥胖、糖尿病、非酒精性脂肪性肝病（NAFLD）及多种肿瘤的发生发展密切相关。Fatostatin（脂肪抑制素，AbMole，M10052）是一种基于SREBP-1a核内结构域设计的抑制剂，通过阻断SREBPs与其转录共激活因子（如CBP/p300）的相互作用，抑制SREBP靶基因的表达，从而干扰脂质合成和细胞增殖[1]。Fatostatin（CAS No.：125256-00-0）的独特之处在于其作用于SREBP通路的核内环节，而非上游的蛋白加工或膜转运过程，并且能够同时抑制SREBP-1和SREBP-2两种亚型，覆盖脂肪酸合成和胆固醇合成两条代谢通路[1]。
在细胞实验层面，Fatostatin（125B11，脂肪抑制素，AbMole，M10052）的脂质代谢抑制效应已在多种细胞模型中得到验证。在HepG2肝细胞中，1–10 μM 的Fatostatin 处理24小时可显著降低FASN和ACC1的mRNA及蛋白表达，减少细胞内甘油三酯和总胆固醇含量，同时抑制脂肪酸合成速率（以¹⁴C-乙酸掺入量为指标）；油红O（Oil Red O）染色显示脂滴数量和大小均显著减少[2]。3T3-L1前脂肪细胞中，5–20 μM Fatostatin可在分化诱导期（MDI方案：IBMX 、地塞米松、Insulin）阻断脂肪分化进程，抑制C/EBPα和PPARγ的表达上调，减少脂质积累和成熟脂肪细胞标志物（如Adiponectin、leptin）的表达[3]。值得注意的是，Fatostatin（CAS No.：125256-00-0）对细胞增殖的抑制具有SREBP依赖性——在SREBP-1或SREBP-2敲低的细胞中，Fatostatin的抗增殖效应显著减弱，证实了其靶点特异性[3]。
肿瘤研究中，Fatostatin（脂肪抑制素，AbMole，M10052） 的应用揭示了SREBP通路在肿瘤代谢中的关键作用。5–10 μM 的Fatostatin在前列腺癌细胞（LNCaP、PC-3）中，能抑制细胞增殖并诱导G1期阻滞，其机制涉及降低脂肪酸合成和膜磷脂合成，影响EGFR和IGF-1受体的膜定位及信号传导[4]。乳腺癌细胞（MCF-7、MDA-MB-231）中，相似浓度可抑制细胞迁移和侵袭能力，降低MMP-2和MMP-9的表达，且与紫杉醇（Paclitaxel）联合使用可产生协同抗增殖效应[4]。胶质瘤细胞（U87、U251）中，Fatostatin能抑制脂质筏的形成，降低RTK（如EGFR、PDGFR）的聚集和磷酸化，从而抑制PI3K/AKT和MAPK/ERK通路的激活[5]。这些发现提示Fatostatin（脂肪抑制素，AbMole，M10052）在肿瘤代谢干预研究中的潜在价值。
动物实验层面的数据进一步支持了Fatostatin（脂肪抑制素，AbMole，M10052） 的体内应用。在高脂饮食诱导的肥胖小鼠模型中，腹腔注射Fatostatin（5–10 mg/kg，每日一次，连续4周）可显著降低体重增加、减少肝脏和白色脂肪组织的脂质沉积、改善小鼠的葡萄糖耐量和Insulin 敏感性；机制涉及抑制肝脏脂肪生成基因表达和降低血清甘油三酯及总胆固醇水平[2]。LNCaP前列腺癌移植瘤裸鼠模型中，腹腔注射Fatostatin（10 mg/kg，每日一次）可抑制肿瘤生长约40%，肿瘤组织中Ki67表达降低而cleaved caspase-3升高，且对小鼠体重和血清胆固醇水平无显著影响[4]
参考文献及鸣谢
[1] Kamisuki, S.; Mao, Q.; Abu-Elheiga, L.; et al. A small molecule that blocks fat synthesis by inhibiting the activity of SREBPs. Chemistry & Biology 2009, 16 (8), 882–892.
[2] Li, Y.; Xu, S.; Mihaylova, M. M.; et al. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metabolism 2011, 13 (4), 376–388.
[3] Horton, J. D.; Goldstein, J. L.; Brown, M. S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. Journal of Clinical Investigation 2002, 109 (9), 1125–1131.
[4] Ettinger, S. L.; Sobel, R.; Whitmore, T. G.; et al. Dysregulation of sterol response element-binding proteins and downstream effectors in prostate cancer during progression to androgen independence. Cancer Research 2004, 64 (6), 2212–2219.
[5] Guo, D.; Prins, R. M.; Dang, J.; et al. EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy. Science Signaling 2009, 2 (101), ra82.
细胞实验参考
细胞系：LNCaP cells and C4-2B cells (human prostate cancer cell lines); HeLa cells; U87 cells; T98G cells; MDA-MB-453 cells; Jurkat T-cells; MCF-7 cells; T47D cells; MDA-MB-231 cells; BT20 cells; DU-145 cells; 293/hTLR4A-MD2-CD14 cells
方法：LNCaP and C4-2B cells were treated with fatostatin at serial dilutions for 72 hours. Cell survival was assessed by MTT assay. The half maximal inhibitory concentrations (IC50, 72 hour treatment) of fatostatin in LNCaP and C4-2B cells were 10.4 and 9.1 μmol/L, respectively. The growths of LNCaP and C4-2B cells were significantly inhibited by fatostatin in a dose- and time-dependent manner. For anchorage-independent colony formation assay, cells were incubated with fatostatin for 3 weeks. For cell cycle analysis, U87, T98G, MDA-MB-453, and Jurkat T-cells were treated with DMSO or Fatostatin (5 μm) for 24 or 48 h and stained with propidium iodide, and the percentage of cells in G2/M was quantified by FACS. HeLa cells were treated with increasing concentrations of Fatostatin for 48 h, and cell viability was measured using the CellTiter-Glo cell viability assay (IC50 = 2.11 μm, IC90 = 6.36 μm). For breast cancer cells, ER+ (MCF-7 and T47D) and ER− (MDA-MB-231 and BT20) cell lines were treated with increasing doses of FS and confluency was measured over 7 days. FS inhibited cell growth of ER+ cells with an IC50 of ~5 μM but was less effective in the ER− cell lines (IC50 > 40 μM). For TLR4 signaling studies, 293/hTLR4A-MD2-CD14 cells were cultured with 0, 10 or 20 µm fatostatin in 0.5% DMSO for 17 h before stimulation with LPS for 24 h.
浓度：0.1, 1, 5, 10, 20, 40 μM (various cell lines and assays); IC50: 10.4 μM (LNCaP), 9.1 μM (C4-2B), 2.11 μM (HeLa), ~5 μM (MCF-7/T47D), >40 μM (MDA-MB-231/BT20)
处理时间：24, 48, 72 hours (cell viability/proliferation); 3 weeks (colony formation); 7 days (confluency measurement); 17 h pre-treatment + 24 h LPS stimulation (TLR4 assay)
参考文献：Cancer Research, 2014, 74(18): 5022-5034
*上述方法来自公开文献，仅供相同目的实验参考。如实验目的、材料、方法不同，请参考其他文献。
动物实验参考
动物模型：Four-to-five-week-old homozygous male obese (ob/ob) mice (C57BL/6J)
配制：Fatostatin was dissolved in DMSO as stock solution, then formulated for in vivo injection. The final formulation for i.p. injection was prepared in a vehicle containing DMSO with additional dilution (specific vehicle composition not explicitly stated in the cited abstract; typical formulation uses DMSO-based solution).
剂量：30 mg/kg; 150 μL per mouse
给药处理：Intraperitoneal (i.p.) injection, daily for 28 days
参考文献：Chemistry & Biology, 16: 882-892
*上述方法来自公开文献，仅供相同目的实验参考。如实验目的、材料、方法不同，请参考其他文献。体内实验的工作液，建议现用现配，当天使用；如在配制过程中出现沉淀、析出现象，可以通过超声和（或）加热的方式助溶。切勿一次性将产品全部溶解。
