The anti-tubercular activity of simvastatin is mediated by cholesterol-driven autophagy via the AMPK-mTORC1-TFEB axis.
The anti-tubercular activity of simvastatin is mediated by cholesterol-driven autophagy via the AMPK-mTORC1-TFEB axis.
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DOI：
10.1194/jlr.ra120000895
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发表时间：
2020-12
影响因子：
6.5
通讯作者：
Gennaro ML
中科院分区：
文献类型：
--
作者：
Bruiners N;Dutta NK;Guerrini V;Salamon H;Yamaguchi KD;Karakousis PC;Gennaro ML
耐药结核病的增加对公共卫生构成重大风险。他汀类药物抑制胆固醇生物合成和甲羟戊酸途径的蛋白戊酰化分支，在动物模型中提高抗结核抗生素的疗效。然而，潜在的分子机制尚不清楚。在本研究中，我们采用体外巨噬细胞感染模型，通过系统抑制甲羟戊酸途径的各个分支，并评估分支特异性抑制剂对分枝杆菌生长的影响，来研究辛伐他汀的抗结核活性。临床相关剂量的辛伐他汀的抗结核活性特异性针对胆固醇生物合成分支，而不是甲羟戊酸途径的戊烯酰化分支。通过Western blot分析和AMP/ATP测量，我们发现辛伐他汀治疗阻断了雷帕霉素复合物1 （mTORC1）的机制靶点的激活，通过增加细胞内AMP:ATP比率激活了AMP活化的蛋白激酶（AMPK），并促进了转录因子EB （TFEB）的核易位。这些机制都能诱导抗分枝杆菌的自噬。通过向细胞中添加外源性胆固醇，辛伐他汀对ampk - mtorc1 - tfeb -自噬轴的生物学效应被逆转。我们的数据表明，辛伐他汀的抗结核活性需要抑制胆固醇的生物合成，揭示了胆固醇稳态、AMPK-mTORC1-TFEB轴和结核分枝杆菌感染控制之间的新联系，并揭示了新的抗结核治疗靶点。
The rise of drug-resistant tuberculosis poses a major risk to public health. Statins, which inhibit both cholesterol biosynthesis and protein prenylation branches of the mevalonate pathway, increase anti-tubercular antibiotic efficacy in animal models. However, the underlying molecular mechanisms are unknown. In this study, we used an in vitro macrophage infection model to investigate simvastatin’s anti-tubercular activity by systematically inhibiting each branch of the mevalonate pathway and evaluating the effects of the branch-specific inhibitors on mycobacterial growth. The anti-tubercular activity of simvastatin used at clinically relevant doses specifically targeted the cholesterol biosynthetic branch rather than the prenylation branches of the mevalonate pathway. Using Western blot analysis and AMP/ATP measurements, we found that simvastatin treatment blocked activation of mechanistic target of rapamycin complex 1 (mTORC1), activated AMP-activated protein kinase (AMPK) through increased intracellular AMP:ATP ratios, and favored nuclear translocation of transcription factor EB (TFEB). These mechanisms all induce autophagy, which is anti-mycobacterial. The biological effects of simvastatin on the AMPK-mTORC1-TFEB-autophagy axis were reversed by adding exogenous cholesterol to the cells. Our data demonstrate that the anti-tubercular activity of simvastatin requires inhibiting cholesterol biosynthesis, reveal novel links between cholesterol homeostasis, the AMPK-mTORC1-TFEB axis, and Mycobacterium tuberculosis infection control, and uncover new anti-tubercular therapy targets.
DOI：
10.1038/tpj.2012.27
发表时间：
2013-10
期刊：
The pharmacogenomics journal
影响因子：
--
作者：
Croze E;Yamaguchi KD;Knappertz V;Reder AT;Salamon H
通讯作者：
Salamon H