The anti-tubercular activity of simvastatin is mediated by cholesterol-driven autophagy via the AMPK-mTORC1-TFEB axis

Natalie Bruiners; Noton K. Dutta; Valentina Guerrini; Hugh Salamon; Ken D. Yamaguchi; Petros C. Karakousis; Maria L. Gennaro

doi:https://doi.org/10.1194/jlr.RA120000895

The anti-tubercular activity of simvastatin is mediated by cholesterol-driven autophagy via the AMPK-mTORC1-TFEB axis

Natalie Bruiners, Noton K. Dutta, Valentina Guerrini, Hugh Salamon, Ken D. Yamaguchi, Petros C. Karakousis, Maria L. Gennaro

New Jersey Medical School (NJMS), Public Health Research Institute Center

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

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.

Original language	American English
Pages (from-to)	1617-1628
Number of pages	12
Journal	Journal of lipid research
Volume	61
Issue number	12
DOIs	https://doi.org/10.1194/jlr.RA120000895
State	Published - Dec 2020

ASJC Scopus subject areas

Biochemistry
Endocrinology
Cell Biology

Keywords

Adenosine 5'-monophosphate-activated protein kinase-mechanistic target of rapamycin complex 1-transcription factor EB axis
Immunology
Lipids
Macrophages/ monocytes
Mechanistic target of rapamycin complex 1 regulation
Mycobacterium tuberculosis
Statins

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@article{66d39a00d2674d49b02675aec4ffc8d5,

title = "The anti-tubercular activity of simvastatin is mediated by cholesterol-driven autophagy via the AMPK-mTORC1-TFEB axis",

abstract = "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.",

keywords = "Adenosine 5'-monophosphate-activated protein kinase-mechanistic target of rapamycin complex 1-transcription factor EB axis, Immunology, Lipids, Macrophages/ monocytes, Mechanistic target of rapamycin complex 1 regulation, Mycobacterium tuberculosis, Statins",

author = "Natalie Bruiners and Dutta, {Noton K.} and Valentina Guerrini and Hugh Salamon and Yamaguchi, {Ken D.} and Karakousis, {Petros C.} and Gennaro, {Maria L.}",

note = "Funding Information: This work was supported by National Institutes of Health Grants UH2/3 AI122309 (P.K.), R01 HL149450 (M.L.G.), R01 AI104615 (M.L.G.), and UL1 TR003017 NCATS (M.L.G.) and New Jersey Health Foundation Grant PC 10-15 (M.L.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2020 Bruiners et al.",

year = "2020",

month = dec,

doi = "https://doi.org/10.1194/jlr.RA120000895",

language = "American English",

volume = "61",

pages = "1617--1628",

journal = "Journal of lipid research",

issn = "0022-2275",

publisher = "American Society for Biochemistry and Molecular Biology Inc.",

number = "12",

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T1 - The anti-tubercular activity of simvastatin is mediated by cholesterol-driven autophagy via the AMPK-mTORC1-TFEB axis

AU - Bruiners, Natalie

AU - Dutta, Noton K.

AU - Guerrini, Valentina

AU - Salamon, Hugh

AU - Yamaguchi, Ken D.

AU - Karakousis, Petros C.

AU - Gennaro, Maria L.

N1 - Funding Information: This work was supported by National Institutes of Health Grants UH2/3 AI122309 (P.K.), R01 HL149450 (M.L.G.), R01 AI104615 (M.L.G.), and UL1 TR003017 NCATS (M.L.G.) and New Jersey Health Foundation Grant PC 10-15 (M.L.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: © 2020 Bruiners et al.

PY - 2020/12

Y1 - 2020/12

N2 - 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.

AB - 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.

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KW - Immunology

KW - Lipids

KW - Macrophages/ monocytes

KW - Mechanistic target of rapamycin complex 1 regulation

KW - Mycobacterium tuberculosis

KW - Statins

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U2 - https://doi.org/10.1194/jlr.RA120000895

DO - https://doi.org/10.1194/jlr.RA120000895

M3 - Article

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SN - 0022-2275

VL - 61

SP - 1617

EP - 1628

JO - Journal of lipid research

JF - Journal of lipid research

IS - 12

ER -

The anti-tubercular activity of simvastatin is mediated by cholesterol-driven autophagy via the AMPK-mTORC1-TFEB axis

Abstract

ASJC Scopus subject areas

Keywords

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