Triglyceride breakdown from lipid droplets regulates the inflammatory response in macrophages

Proceedings of the National Academy of Sciences, vol. 119, pp. e2114739119

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.

Authors 11

1. Xanthe A.M.H. van Dierendonck

   Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences · Wageningen University & Research

   Affiliation as printed

   Department of Internal Medicine (463), Radboud University Medical Center, 6525GA Nijmegen, The Netherlands

   Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708WE Wageningen, The Netherlands

   Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525GA Nijmegen, The Netherlands

   Department of Internal Medicine (463), Radboud University Medical Center, 6525GA Nijmegen, The Netherlands;

   Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708WE Wageningen, The Netherlands;

   Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525GA Nijmegen, The Netherlands;

2. Frank Vrieling

   Wageningen University & Research

   Affiliation as printed

   Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708WE Wageningen, The Netherlands

   Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708WE Wageningen, The Netherlands;

3. Lisa Smeehuijzen

   Wageningen University & Research

   Affiliation as printed

   Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708WE Wageningen, The Netherlands

   Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708WE Wageningen, The Netherlands;

4. Lei Deng

   Wageningen University & Research

   Affiliation as printed

   Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708WE Wageningen, The Netherlands

   Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708WE Wageningen, The Netherlands;

5. Joline P. Boogaard

   Wageningen University & Research

   Affiliation as printed

   Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708WE Wageningen, The Netherlands

   Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708WE Wageningen, The Netherlands;

6. Cresci-Anne Croes

   Wageningen University & Research

   Affiliation as printed

   Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708WE Wageningen, The Netherlands

   Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708WE Wageningen, The Netherlands;

7. Lieve Temmerman

   Maastricht University

   Affiliation as printed

   Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, 6211LK Maastricht, The Netherlands

   Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, 6211LK Maastricht, The Netherlands;

8. Suzan Wetzels

   Maastricht University

   Affiliation as printed

   Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, 6211LK Maastricht, The Netherlands

   Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, 6211LK Maastricht, The Netherlands;

9. Erik A.L. Biessen Aachen Institute for Molecular Cardiology

   Maastricht University · Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, 6211LK Maastricht, The Netherlands

   Institute for Molecular Cardiology, Klinikum Rheinisch Westfälische Technische Hochschule Aachen, Aachen, 52074 Germany

   Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, 6211LK Maastricht, The Netherlands;

10. Sander Kersten

    Wageningen University & Research

    Affiliation as printed

    Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708WE Wageningen, The Netherlands

    Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708WE Wageningen, The Netherlands;

11. Rinke Stienstra corresponding

    Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences · Wageningen University & Research

    Affiliation as printed

    Department of Internal Medicine (463), Radboud University Medical Center, 6525GA Nijmegen, The Netherlands

    Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708WE Wageningen, The Netherlands

    Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525GA Nijmegen, The Netherlands

    Department of Internal Medicine (463), Radboud University Medical Center, 6525GA Nijmegen, The Netherlands;

    Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708WE Wageningen, The Netherlands;

    Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525GA Nijmegen, The Netherlands;