Abstract 18303: Lrp1 Regulates Metabolic Activity by Binding PPAR Gamma in Endothelium
Introduction: The endothelium is a biologically active barrier and the site of metabolic exchange between the circulation and underlying tissues. Endothelial dysfunction is a common feature for obesity, dyslipidemia and diabetes and other vascular related diseases. Our recent studies demonstrate that low density lipoprotein receptor-related protein 1 (LRP1) impacts a variety of biological processes such as lipid metabolism, endocytosis and signal transduction. However, the role of LRP1 in endothelial cells remains a mystery.
Methods & Results: The LRP1flox/flox (LRP1f/f) mouse was bred to Tie2-Cre transgenic mouse to have LRP1 deleted in ECs and hematopoietic cells, resulting in inactivation of LRP1 gene function in these cells only. Both the LRP1f/f;Tie2Cre+ mice and wild type mice were fed with high fat diet for 16 weeks. The LRP1f/f;Tie2Cre+ mice displayed a smaller increase in adipose tissue weight, liver weight and body weight , compared to wild-type mice following high fat food feeding. In addition, we discovered that adipocyte size is significantly smaller in LRP1f/f;Tie2Cre+ mice than wild type mice. In addition, LRP1f/f;Tie2Cre+ mice are more sensitive to insulin following a bolus of glucose, demonstrated with the decreased glucose level in serum. The LRP1f/f;Tie2Cre+ mice also had decreased levels of circulating resistin, adiponectin and leptin compared to wild type mice. In LRP1f/f;Tie2Cre+mouse liver, there are much less deposition of lipid droplets than the wild type liver. The study of lipid profiles shows a much smaller increase in cholesterol and HDL levels. In cultured mouse endothelial cells (MECs), we discovered that LRP1 binds PPARγ, an important protein that is known to regulate endothelium function and contribute to the regulation of systemic metabolic responses. LRP1 positively regulates PPARγ activity and affects lipid handling gene induction in MECs.
Conclusions: Taken all together, our data suggest that endothelial LRP1 regulates systemic metabolic events possibly through binding PPARγ and thereby modulating endothelial activation. It provides novel mechanistic insights for the metabolic roles of endothelial LRP1 and expands the functional roles of endothelium.
- Low density lipoprotein receptor-related protein1
- systemic metabolic responses
- endothelial activation
Author Disclosures: H. Mao: None. X. Li: None. P. Lockyer: None. L. Xie: None. X. Pi: None.
- © 2015 by American Heart Association, Inc.