Lysosomal lipoprotein processing in endothelial cells stimulates adipose tissue thermogenic adaptation
Lysosomal lipoprotein processing in endothelial cells stimulates adipose tissue thermogenic adaptation
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DOI：
10.1016/j.cmet.2020.12.001
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发表时间：
2021-03-02
期刊：
影响因子：
29
通讯作者：
Heeren, Joerg
中科院分区：
文献类型：
--
作者：
Fischer, Alexander W.;Jaeckstein, Michelle Y.;Heeren, Joerg
在棕色脂肪组织（BAT）和白色脂肪组织（WAT）的毛细血管腔中，在脂蛋白脂肪酶介导的富甘油三酯脂蛋白（TRL）水解后，产热脂肪细胞对冷暴露的反应是内化大量脂肪酸。在这里，我们表明，在冷暴露的小鼠，脂肪组织中的血管内皮细胞内吞大量的整个TRL颗粒。这些脂蛋白随后遵循内体-溶酶体途径，其中它们经历溶酶体酸性脂肪酶（LAL）介导的加工。内皮细胞特异性LAL缺乏导致产热能力受损，这是棕色和浅褐色/米色脂肪细胞募集减少的结果。从机制上讲，LAL对TRL的加工通过活性氧的β-氧化依赖性产生诱导内皮细胞和脂肪细胞前体的增殖，进而刺激缺氧诱导因子-1 α依赖性增殖反应。总之，这项研究表明，TRL颗粒摄取到BAT和WAT的生理作用，并建立内皮脂蛋白加工作为一个重要的决定因素，脂肪组织重塑产热适应。
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-1 alpha-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.