Lysosomal lipoprotein processing in endothelial cells stimulates adipose tissue thermogenic adaptation

• Published in: Cell metabolism 2021-03, Vol.33 (3), p.547-564.e7
• Main Authors: Fischer, Alexander W., Jaeckstein, Michelle Y., Gottschling, Kristina, Heine, Markus, Sass, Frederike, Mangels, Nils, Schlein, Christian, Worthmann, Anna, Bruns, Oliver T., Yuan, Yucheng, Zhu, Hua, Chen, Ou, Ittrich, Harald, Nilsson, Stefan K., Stefanicka, Patrik, Ukropec, Jozef, Balaz, Miroslav, Dong, Hua, Sun, Wenfei, Reimer, Rudolf, Scheja, Ludger, Heeren, Joerg
• Format: Article
• Language: English
• Subjects: Adiponectin - genetics; Adiponectin - metabolism; Adipose Tissue, Brown - metabolism; Adipose Tissue, Brown - pathology; Adipose Tissue, White - metabolism; Adipose Tissue, White - pathology; angiogenesis; Animals; beige adipocytes; brown adipose tissue; CD36 Antigens - metabolism; Cell Differentiation; Cell Proliferation; Cold Temperature; endothelial cells; Endothelial Cells - cytology; Endothelial Cells - metabolism; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; hypoxia-inducible factor 1α; lipoproteins; Lipoproteins - genetics; Lipoproteins - metabolism; lysosomal acid lipase; Lysosomes - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Reactive Oxygen Species - metabolism; Receptors, Lipoprotein - genetics; Receptors, Lipoprotein - metabolism; Sterol Esterase - deficiency; Sterol Esterase - genetics; Sterol Esterase - metabolism; Thermogenesis; triglycerides; Triglycerides - genetics; Triglycerides - metabolism; white adipose tissue
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2020.12.001

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. [Display omitted] •Endothelial cells of cold-activated BAT and WAT endocytose lipoprotein particles•These triglyceride-rich lipoproteins are processed by LAL•Subsequently, HIF1α is activated via fatty-acid oxidation and ROS production•Endothelial LAL deficiency impairs vascularization and thermogenesis in BAT and WAT Fischer et al. reveal that endothelial cells of cold-activated BAT and WAT internalize entire triglyceride-rich lipoprotein particles that are targeted toward lysosomes and processed by lysosomal acid lipase. Then, mitochondrial beta-oxidation leads to ROS-dependent HIF1α activation, which promotes vascular and thermogenic remodeling of adipose tissues.