Triglyceride breakdown from lipid droplets regulates the inflammatory response in macrophages

X.A.M.H. van Dierendonck; F. Vrieling; L. Smeehuijzen; L. Deng; J.P. Boogaard; C.A. Croes; L. Temmerman; S. Wetzels; E. Biessen; S. Kersten; R. Stienstra

doi:10.1073/pnas.2114739119

Triglyceride breakdown from lipid droplets regulates the inflammatory response in macrophages

X.A.M.H. van Dierendonck, F. Vrieling, L. Smeehuijzen, L. Deng, J.P. Boogaard, C.A. Croes, L. Temmerman, S. Wetzels, E. Biessen, S. Kersten, R. Stienstra^*

^*Corresponding author for this work

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

Abstract

In response to inflammatory activation by pathogens, macrophages accumulate triglycerides in intracellular lipid droplets. The mechanisms underlying triglyceride accumulation and its exact role in the inflammatory response of macrophages are not fully understood. Here, we aim to further elucidate the mechanism and function of triglyceride accumulation in the inflammatory response of activated macrophages. Lipopolysaccharide (LPS)-mediated activation markedly increased triglyceride accumulation in macrophages. This increase could be attributed to up-regulation of the hypoxia-inducible lipid droplet-associated (HILPDA) protein, which down-regulated adipose triglyceride lipase (ATGL) protein levels, in turn leading to decreased ATGL-mediated triglyceride hydrolysis. The reduction in ATGL-mediated lipolysis attenuated the inflammatory response in macrophages after ex vivo and in vitro activation, and was accompanied by decreased production of prostaglandin-E2 (PGE2) and interleukin-6 (IL-6). Overall, we provide evidence that LPS-mediated activation of macrophages suppresses lipolysis via induction of HILPDA, thereby reducing the availability of proinflarnmatory lipid precursors and suppressing the production of PGE2 and IL-6.

Original language	English
Article number	e2114739119
Number of pages	12
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	119
Issue number	12
DOIs	https://doi.org/10.1073/pnas.2114739119
Publication status	Published - 22 Mar 2022

Keywords

immunometabolism
lipid droplets
macrophages
HILPDA
ATGL
TNF-ALPHA
STIMULATES LIPOLYSIS
PROSTAGLANDIN E-2
ADIPOSE-TISSUE
INTERLEUKIN-6
PROTEIN
LIPASE
EXPRESSION
ACCUMULATION
METABOLISM

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van Dierendonck, X. A. M. H., Vrieling, F., Smeehuijzen, L., Deng, L., Boogaard, J. P., Croes, C. A., Temmerman, L., Wetzels, S., Biessen, E., Kersten, S., & Stienstra, R. (2022). Triglyceride breakdown from lipid droplets regulates the inflammatory response in macrophages. Proceedings of the National Academy of Sciences of the United States of America, 119(12), Article e2114739119. https://doi.org/10.1073/pnas.2114739119

@article{4073cfa2330a40caba97617d6e136ab5,

title = "Triglyceride breakdown from lipid droplets regulates the inflammatory response in macrophages",

abstract = "In response to inflammatory activation by pathogens, macrophages accumulate triglycerides in intracellular lipid droplets. The mechanisms underlying triglyceride accumulation and its exact role in the inflammatory response of macrophages are not fully understood. Here, we aim to further elucidate the mechanism and function of triglyceride accumulation in the inflammatory response of activated macrophages. Lipopolysaccharide (LPS)-mediated activation markedly increased triglyceride accumulation in macrophages. This increase could be attributed to up-regulation of the hypoxia-inducible lipid droplet-associated (HILPDA) protein, which down-regulated adipose triglyceride lipase (ATGL) protein levels, in turn leading to decreased ATGL-mediated triglyceride hydrolysis. The reduction in ATGL-mediated lipolysis attenuated the inflammatory response in macrophages after ex vivo and in vitro activation, and was accompanied by decreased production of prostaglandin-E2 (PGE2) and interleukin-6 (IL-6). Overall, we provide evidence that LPS-mediated activation of macrophages suppresses lipolysis via induction of HILPDA, thereby reducing the availability of proinflarnmatory lipid precursors and suppressing the production of PGE2 and IL-6.",

keywords = "immunometabolism, lipid droplets, macrophages, HILPDA, ATGL, TNF-ALPHA, STIMULATES LIPOLYSIS, PROSTAGLANDIN E-2, ADIPOSE-TISSUE, INTERLEUKIN-6, PROTEIN, LIPASE, EXPRESSION, ACCUMULATION, METABOLISM",

author = "{van Dierendonck}, X.A.M.H. and F. Vrieling and L. Smeehuijzen and L. Deng and J.P. Boogaard and C.A. Croes and L. Temmerman and S. Wetzels and E. Biessen and S. Kersten and R. Stienstra",

note = "Funding Information: We thank Merel Defour, Benthe van der Lugt, Julia van Heck, Jenny Jansen, Anneke Hijmans, Gregorio Fazzi, and Ricky Siebeler for their practical assistance and Dr. Christina Warnecke for providing the HILPDA antibody. This work was financed by grants from the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (2014/12393/ALW), Diabetes Fonds (2015.82.1824), and Hartstichting (ENERGISE CVON2014-02). Funding Information: ACKNOWLEDGMENTS. We thank Merel Defour, Benthe van der Lugt, Julia van Heck, Jenny Jansen, Anneke Hijmans, Gregorio Fazzi, and Ricky Siebeler for their practical assistance and Dr. Christina Warnecke for providing the HILPDA antibody. This work was financed by grants from the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (2014/12393/ALW), Diabetes Fonds (2015.82.1824), and Hartstichting (ENERGISE CVON2014-02). Publisher Copyright: Copyright {\textcopyright} 2022 the Author(s).",

year = "2022",

month = mar,

day = "22",

doi = "10.1073/pnas.2114739119",

language = "English",

volume = "119",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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van Dierendonck, XAMH, Vrieling, F, Smeehuijzen, L, Deng, L, Boogaard, JP, Croes, CA, Temmerman, L, Wetzels, S, Biessen, E, Kersten, S & Stienstra, R 2022, 'Triglyceride breakdown from lipid droplets regulates the inflammatory response in macrophages', Proceedings of the National Academy of Sciences of the United States of America, vol. 119, no. 12, e2114739119. https://doi.org/10.1073/pnas.2114739119

TY - JOUR

T1 - Triglyceride breakdown from lipid droplets regulates the inflammatory response in macrophages

AU - van Dierendonck, X.A.M.H.

AU - Vrieling, F.

AU - Smeehuijzen, L.

AU - Deng, L.

AU - Boogaard, J.P.

AU - Croes, C.A.

AU - Temmerman, L.

AU - Wetzels, S.

AU - Biessen, E.

AU - Kersten, S.

AU - Stienstra, R.

N1 - Funding Information: We thank Merel Defour, Benthe van der Lugt, Julia van Heck, Jenny Jansen, Anneke Hijmans, Gregorio Fazzi, and Ricky Siebeler for their practical assistance and Dr. Christina Warnecke for providing the HILPDA antibody. This work was financed by grants from the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (2014/12393/ALW), Diabetes Fonds (2015.82.1824), and Hartstichting (ENERGISE CVON2014-02). Funding Information: ACKNOWLEDGMENTS. We thank Merel Defour, Benthe van der Lugt, Julia van Heck, Jenny Jansen, Anneke Hijmans, Gregorio Fazzi, and Ricky Siebeler for their practical assistance and Dr. Christina Warnecke for providing the HILPDA antibody. This work was financed by grants from the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (2014/12393/ALW), Diabetes Fonds (2015.82.1824), and Hartstichting (ENERGISE CVON2014-02). Publisher Copyright: Copyright © 2022 the Author(s).

PY - 2022/3/22

Y1 - 2022/3/22

N2 - In response to inflammatory activation by pathogens, macrophages accumulate triglycerides in intracellular lipid droplets. The mechanisms underlying triglyceride accumulation and its exact role in the inflammatory response of macrophages are not fully understood. Here, we aim to further elucidate the mechanism and function of triglyceride accumulation in the inflammatory response of activated macrophages. Lipopolysaccharide (LPS)-mediated activation markedly increased triglyceride accumulation in macrophages. This increase could be attributed to up-regulation of the hypoxia-inducible lipid droplet-associated (HILPDA) protein, which down-regulated adipose triglyceride lipase (ATGL) protein levels, in turn leading to decreased ATGL-mediated triglyceride hydrolysis. The reduction in ATGL-mediated lipolysis attenuated the inflammatory response in macrophages after ex vivo and in vitro activation, and was accompanied by decreased production of prostaglandin-E2 (PGE2) and interleukin-6 (IL-6). Overall, we provide evidence that LPS-mediated activation of macrophages suppresses lipolysis via induction of HILPDA, thereby reducing the availability of proinflarnmatory lipid precursors and suppressing the production of PGE2 and IL-6.

AB - In response to inflammatory activation by pathogens, macrophages accumulate triglycerides in intracellular lipid droplets. The mechanisms underlying triglyceride accumulation and its exact role in the inflammatory response of macrophages are not fully understood. Here, we aim to further elucidate the mechanism and function of triglyceride accumulation in the inflammatory response of activated macrophages. Lipopolysaccharide (LPS)-mediated activation markedly increased triglyceride accumulation in macrophages. This increase could be attributed to up-regulation of the hypoxia-inducible lipid droplet-associated (HILPDA) protein, which down-regulated adipose triglyceride lipase (ATGL) protein levels, in turn leading to decreased ATGL-mediated triglyceride hydrolysis. The reduction in ATGL-mediated lipolysis attenuated the inflammatory response in macrophages after ex vivo and in vitro activation, and was accompanied by decreased production of prostaglandin-E2 (PGE2) and interleukin-6 (IL-6). Overall, we provide evidence that LPS-mediated activation of macrophages suppresses lipolysis via induction of HILPDA, thereby reducing the availability of proinflarnmatory lipid precursors and suppressing the production of PGE2 and IL-6.

KW - immunometabolism

KW - lipid droplets

KW - macrophages

KW - HILPDA

KW - ATGL

KW - TNF-ALPHA

KW - STIMULATES LIPOLYSIS

KW - PROSTAGLANDIN E-2

KW - ADIPOSE-TISSUE

KW - INTERLEUKIN-6

KW - PROTEIN

KW - LIPASE

KW - EXPRESSION

KW - ACCUMULATION

KW - METABOLISM

U2 - 10.1073/pnas.2114739119

DO - 10.1073/pnas.2114739119

M3 - Article

C2 - 35302892

SN - 0027-8424

VL - 119

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 12

M1 - e2114739119

ER -