Mechanism of action underlying SREBP in different diseases and its targeted inhibition for disease prevention and treatment.

IntroductionAdipose tissue regulates metabolic homeostasis and serves as a reservoir for mesenchymal stem cells (MSCs), which differentiate into osteoblasts ...

Recent evidence suggests that cellular metabolism, including glycolysis and fatty acid synthesis in lymphatic endothelial cells (LECs), plays essential roles in developing functional lymphatic systems. Site-1 protease (S1P) proteolytically activates membrane-bound latent transcription factor sterol regulatory element-binding proteins (SREBPs), which are required to induce lipid biosynthesis. In this study, we generated mice with pan-endothelial or LEC-specific deficiency of either S1P or SREBP2. Mouse embryos with pan-endothelial deletion of S1P showed defective lymphatic vessel migration in skin and lymphedema, while their blood vasculature formation was relatively normal. Mice lacking S1P in LECs or SREBP2 in LECs exhibited chylous ascites, reduced lipogenic gene expression, and reduced VEGFR3 expression and progressively developed wasting, resulting in postnatal death by approximately 8 weeks of age. Additionally, mice with SREBP2 deletion in LECs exhibited dilated lacteal and mesenteric lymphatics and accumulation of lipids in the lacteal before weaning age, indicating apparent lymphatic malfunctioning. These data indicate that S1P-SREBP2–mediated cholesterol biosynthesis is pivotal in lymphatic vascular development. We also found that treating human dermal LECs with VEGF-C induced proteolytic activation of SREBP2 with concomitant phosphorylation of Akt and the expression of genes involved in cholesterol biosynthesis. Those effects were canceled out by treating the cells with an S1P inhibitor or SREBP inhibitor. These data demonstrate that the S1P/SREBP2 axis is critical in VEGF-C/VEGFR3 mitogenic signaling in LECs.

Sterol regulatory element-binding proteins (SREBPs) are a family of transcription factors known to r

Sterol regulatory element-binding proteins (SREBPs) are a family of transcription factors known to r