Gout is a multifaceted inflammatory disease involving vascular impairments induced by hyperuricemia. Experiments using human umbilical vein endothelial cells treated with uric acid (UA), monosodium urate (MSU), or serum from gout patients showed increased expression of pro-inflammatory genes (ie, VCAM1, ICAM1, CYR61, CCNA1, and E2F1) with attendant increase in monocyte adhesion. Mechanistically, UA-or MSU-induced SREBP2 expression and its transcriptional activity. RNA sequencing analysis and real-time PCR showed the induction of YAP signaling and pro-inflammatory pathways in HUVECs transfected with adenovirus-SREBP2. The How to cite this article: Zhao Z, Zhao Y, Zhang Y, et al. Gout-induced endothelial impairment: The role of SREBP2 transactivation of YAP.
Background Plg‐RKT, a unique transmembrane plasminogen receptor, enhances the activation of plasminogen to plasmin, and localizes the proteolytic activity of plasmin on the cell surface. Objectives We investigated the role of Plg‐RKT in adipose function, metabolic homeostasis, and obesity. Methods We used adipose tissue (AT) sections from bariatric surgery patients and from high fat diet (HFD)‐induced obese mice together with immunofluorescence and real‐time polymerase chain reaction to study adipose expression of Plg‐RKT. Mice genetically deficient in Plg‐RKT and littermate controls fed a HFD or control low fat diet (LFD) were used to determine the role of Plg‐RKT in insulin resistance, glucose tolerance, type 2 diabetes, and associated mechanisms including adipose inflammation, fibrosis, and ectopic lipid storage. The role of Plg‐RKT in adipogenesis was determined using 3T3‐L1 preadipocytes and primary cultures established from Plg‐RKT–deficient and littermate control mice. Results Plg‐RKT was highly expressed in both human and mouse AT, and its levels dramatically increased during adipogenesis. Plg‐RKT–deficient mice, when fed a HFD, gained more weight, developed more hepatic steatosis, and were more insulin resistant/glucose intolerant than HFD‐fed wild‐type littermates. Mechanistically, these metabolic defects were linked with increased AT inflammation, AT macrophage and T‐cell accumulation, adipose and hepatic fibrosis, and decreased insulin signaling in the AT and liver. Moreover, Plg‐RKT regulated the expression of PPARγ and other adipogenic molecules, suggesting a novel role for Plg‐RKT in the adipogenic program. Conclusions Plg‐RKT coordinately regulates multiple aspects of adipose function that are important to maintain efficient metabolic homeostasis.
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