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Fischer, A.W.* ; Jaeckstein, M.Y.* ; Gottschling, K.* ; Heine, M.* ; Sass, F.* ; Mangels, N.* ; Schlein, C.* ; Worthmann, A.* ; Bruns, O.T. ; Yuan, Y.* ; Zhu, H.* ; Chen, O.* ; Ittrich, H.* ; Nilsson, S.K.* ; Stefanicka, P.* ; Ukropec, J.* ; Balaz, M.* ; Dong, H.* ; Sun, W.* ; Reimer, R.* ; Scheja, L.* ; Heeren, J.*

Lysosomal lipoprotein processing in endothelial cells stimulates adipose tissue thermogenic adaptation.

Cell Metab. 33, 547-564.e7 (2021)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Angiogenesis ; Beige Adipocytes ; Brown Adipose Tissue ; Endothelial Cells ; Hypoxia-inducible Factor 1α ; Lipoproteins ; Lysosomal Acid Lipase ; Thermogenesis ; Triglycerides ; White Adipose Tissue; Growth-factor; Metabolic Homeostasis; Acid Lipase; Vegf-a; Brown; White; Hypoxia; Mice; Angiogenesis; Adipocytes

ISSN (print) / ISBN 1550-4131

e-ISSN 1932-7420

Journal Cell Metabolism

Quellenangaben Volume: 33, Issue: 3, Pages: 547-564.e7

Publisher Elsevier

Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Helmholtz Pioneer Campus (HPC)

Grants Brown University startup fund
HFSP
DACH Gesellschaft fur Lipidologie
DFG
BMBF
Schering foundation
Muhlbauer Stiftung
Gertraud und Heinz Rose Stiftung
UKE MD/PhD program
German National Academic Foundation, DFG