Abstract 695: Low-density Lipoprotein Receptor-related Protein in the Endothelium Regulates Metabolic Responses
The endothelium, a biologically active barrier, is the site of metabolic exchange between circulation and underlying tissues. Endothelial dysfunction is a common feature in obesity, dyslipidemia and diabetes. Yet the roles endothelial cells play in systemic metabolic responses are unclear. A recent study showed that PPARγ in the endothelium regulates metabolic responses to high fat diet in mice, suggesting that endothelial cells may play a direct role in regulation of obesity, lipid metabolism and insulin sensitivity. Our studies demonstrate that Low-density lipoprotein receptor-related protein 1 (LRP1), a member of LDL receptor family, influences many biological processes such as lipid metabolism, endocytosis and signal transduction, is required for endothelial functions. More interestingly, we discovered that LRP1 interacts with and positively regulates PPARγ activity. Therefore, we wanted to investigate the role of endothelial cell-specific LRP1 in the regulation of systemic metabolic responses. To do this, we used mice deficient in LRP1 in the endothelium and fed a high-fat diet. After 12 weeks of feeding, we found LRP1EC-KO mice to be more sensitive to insulin following a glucose bolus, demonstrated by decreased glucose level in serum (LRP1EC-KO=114.4±15.59 mg/dL glucose; LRP1EC-WT=157.60±14.64 mg/dL glucose). These LRP1EC-KO mice exhibited a smaller increase in body weight (LRP1EC-KO=34.65±2.996g; LRP1EC-WT=44.55±1.752g) compared to wild-type mice following high fat food feeding. In addition to these findings, The composition of white adipose tissue such as the inguinal fat in LRP1EC-KO mice are only 3.9±1.42% of total body weight compared to 6.37±0.342% of total body weight in LRP1EC-WT mice. The levels of circulating leptin and resistin, factors associated with adipogenesis, were also significantly different, with leptin at 7419.25±2031.197 pg/ml in LRP1EC-KO; 16496.2±1921.146 pg/ml in LRP1EC-WT mice; and resistin at 6033.55±3034.54pg/ml in LRP1EC-KO; 17382.6±2894.95pg/ml in LRP1EC-WT mice. Taken all together, our data demonstrate a previously unrecognized role for endothelial cell-specific LRP1, very similar to PPARγ, in regulating systemic metabolic responses, thus expanding the functional roles of endothelium.
Author Disclosures: P. Lockyer: None. H. Mao: None. X. Pi: None.
- © 2015 by American Heart Association, Inc.