2. Academic Validation
  3. Lysosomal lipoprotein processing in endothelial cells stimulates adipose tissue thermogenic adaptation

Lysosomal lipoprotein processing in endothelial cells stimulates adipose tissue thermogenic adaptation

  • Cell Metab. 2021 Mar 2;33(3):547-564.e7. doi: 10.1016/j.cmet.2020.12.001.
Alexander W Fischer 1,  Michelle Y Jaeckstein 2,  Kristina Gottschling 2,  Markus Heine 2,  Frederike Sass 2,  Nils Mangels 2,  Christian Schlein 2,  Anna Worthmann 2,  Oliver T Bruns 3,  Yucheng Yuan 4,  Hua Zhu 4,  Ou Chen 4,  Harald Ittrich 5,  Stefan K Nilsson 6,  Patrik Stefanicka 7,  Jozef Ukropec 8,  Miroslav Balaz 9,  Hua Dong 9,  Wenfei Sun 9,  Rudolf Reimer 10,  Ludger Scheja 2,  Joerg Heeren 11
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • 2 Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 3 Helmholtz Pioneer Campus, Helmholtz Zentrum München, Neuherberg, Germany.
  • 4 Department of Chemistry, Brown University, Providence, RI, USA.
  • 5 Department of Diagnostic and Interventional Radiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 6 Department of Medical Biosciences, Umeå University, Umeå, Sweden.
  • 7 Department of Otorhinolaryngology - Head and Neck Surgery, Comenius University, Bratislava, Slovakia.
  • 8 Institute of Experimental Endocrinology, Biomedical Research Center at the Slovak Academy of Sciences, Bratislava, Slovakia.
  • 9 Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland.
  • 10 Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
  • 11 Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: [email protected].
PMID: 33357458 DOI: 10.1016/j.cmet.2020.12.001
Abstract

In response to cold exposure, thermogenic adipocytes internalize large amounts of fatty acids after lipoprotein lipase-mediated hydrolysis of triglyceride-rich lipoproteins (TRL) in the capillary lumen of brown adipose tissue (BAT) and white adipose tissue (WAT). Here, we show that in cold-exposed mice, vascular endothelial cells in adipose tissues endocytose substantial amounts of entire TRL particles. These lipoproteins subsequently follow the endosomal-lysosomal pathway, where they undergo lysosomal acid Lipase (LAL)-mediated processing. Endothelial cell-specific LAL deficiency results in impaired thermogenic capacity as a consequence of reduced recruitment of brown and brite/beige adipocytes. Mechanistically, TRL processing by LAL induces proliferation of endothelial cells and adipocyte precursors via beta-oxidation-dependent production of Reactive Oxygen Species, which in turn stimulates hypoxia-inducible factor-1α-dependent proliferative responses. In conclusion, this study demonstrates a physiological role for TRL particle uptake into BAT and WAT and establishes endothelial lipoprotein processing as an important determinant of adipose tissue remodeling during thermogenic adaptation.

Keywords

angiogenesis; beige adipocytes; brown adipose tissue; endothelial cells; hypoxia-inducible factor 1α; lipoproteins; lysosomal acid lipase; thermogenesis; triglycerides; white adipose tissue.

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