FSP27: A Novel Modulator of Endothelial Function Through VEGFA Regulation

Fat Specific Protein 27 (FSP27), originally identified as a lipid droplet-associated protein in adipocytes responsible for regulating lipid homeostasis, has recently been shown to play a critical role in endothelial cell function and vascular regulation. In this study, we investigated the physiological effects and molecular mechanisms of endothelial specific FSP27, utilizing a humanized mouse model expressing endothelial-specific human FSP27 (E-FSP27tg) and complementary in vitro approaches. E-FSP27tg mice demonstrated significant protection against high-fat diet-induced metabolic dysfunctions, including glucose intolerance, insulin resistance, and dyslipidemia. These mice also exhibited enhanced endothelial nitric oxide synthase activation, and increased vascularization in adipose tissue, skeletal muscle, and the heart. Mechanistically, we identified a novel interplay between FSP27, vascular endothelial growth factor A (VEGFA), and VEGF receptor 2 (VEGFR2). FSP27 directly binds to and stabilizes VEGFA through post-translational modifications, reducing VEGFA and VEGFR2 degradation, thereby enhancing VEGFR2 activation. Additionally, FSP27 regulates VEGFA transcription via the PPARγ axis. These results highlight the protective role of endothelial FSP27 against obesity-induced metabolic and vascular dysfunctions, partly through the modulation of VEGF signaling. Our finding suggests that FSP27 could serve as a promising therapeutic target for the treatment of obesity-related cardiometabolic diseases. 1R01HL140836 NIH/NHLBI, 1R01DK138635 NIH/NIDDK This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.