Triglyceride breakdown from lipid droplets regulates the inflammatory response in macrophages

Xanthe A M H van Dierendonck; Frank Vrieling; Lisa Smeehuijzen; Lei Deng; Joline P Boogaard; Cresci-Anne Croes; Lieve Temmerman; Suzan Wetzels; Erik Biessen; Sander Kersten; Rinke Stienstra

doi:10.1073/pnas.2114739119

Triglyceride breakdown from lipid droplets regulates the inflammatory response in macrophages

Xanthe A M H van Dierendonck
, Frank Vrieling
, Lisa Smeehuijzen
, Lei Deng
, Joline P Boogaard
, Cresci-Anne Croes
, Lieve Temmerman
, Suzan Wetzels
, Erik Biessen
, Sander Kersten
, Rinke Stienstra

Wageningen University, 6708 PB Wageningen, The Netherlands; Netherlands Institute of Ecology, 6708 PB Wageningen, The Netherlands.
Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands; Department of Clinical Epidemiology and Medical Technology Assessment, School for Public Health and Primary Care, Maastricht University, Maastricht, Netherlands; Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands.

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

36 Downloads (Pure)

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 proinflammatory lipid precursors and suppressing the production of PGE2 and IL-6.

Original language	English
Article number	e2114739119
Pages (from-to)	e2114739119
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
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

ATGL
HILPDA
immunometabolism
lipid droplets
macrophages

Access to Document

10.1073/pnas.2114739119

Triglyceride-breakdown-from-lipid-droplets-regulates-the-inflammatory-response-in-macrophages.pdfFinal published version, 2.5 MB

Cite this

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), e2114739119. Article e2114739119. https://doi.org/10.1073/pnas.2114739119

@article{e23a2ca34f7c4ba5a845707ffbe70a11,

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 proinflammatory lipid precursors and suppressing the production of PGE2 and IL-6.",

keywords = "ATGL, HILPDA, immunometabolism, lipid droplets, macrophages",

author = "\{van Dierendonck\}, \{Xanthe A M H\} and Frank Vrieling and Lisa Smeehuijzen and Lei Deng and Boogaard, \{Joline P\} and Cresci-Anne Croes and Lieve Temmerman and Suzan Wetzels and Erik Biessen and Sander Kersten and Rinke 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",

pages = "e2114739119",

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

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "12",

}

van Dierendonck, XAMH, Vrieling, F, Smeehuijzen, L, Deng, L, Boogaard, JP, 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, vol. 119, no. 12, e2114739119, pp. e2114739119. https://doi.org/10.1073/pnas.2114739119

Triglyceride breakdown from lipid droplets regulates the inflammatory response in macrophages. / van Dierendonck, Xanthe A M H; Vrieling, Frank; Smeehuijzen, Lisa et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 119, No. 12, e2114739119, 22.03.2022, p. e2114739119.

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

TY - JOUR

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

AU - van Dierendonck, Xanthe A M H

AU - Vrieling, Frank

AU - Smeehuijzen, Lisa

AU - Deng, Lei

AU - Boogaard, Joline P

AU - Croes, Cresci-Anne

AU - Temmerman, Lieve

AU - Wetzels, Suzan

AU - Biessen, Erik

AU - Kersten, Sander

AU - Stienstra, Rinke

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 proinflammatory 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 proinflammatory lipid precursors and suppressing the production of PGE2 and IL-6.

KW - ATGL

KW - HILPDA

KW - immunometabolism

KW - lipid droplets

KW - macrophages

UR - https://www.scopus.com/pages/publications/85126723823

U2 - 10.1073/pnas.2114739119

DO - 10.1073/pnas.2114739119

M3 - Article

SN - 0027-8424

VL - 119

SP - e2114739119

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 -

Triglyceride breakdown from lipid droplets regulates the inflammatory response in macrophages

Abstract

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Cite this