Abstract 16524: A Metalloendopeptidase Nardilysin Controls Lipid and Glucose Metabolism Through the Modulation of PPAR-alpha Activity
Nardilysin (N-arginine dibasic convertase (NRDc)), a metalloendopeptidase of the M16 family, is a potent activator for ectodomain shedding of multiple membrane proteins. We have recently reported that NRDc regulates axonal maturation and myelination in the central and peripheral nervous system, but the role of NRDc in lipid and glucose metabolism has not been clarified. Homozygous mutant of NRDc-deficient mice (NRDc−/−) showed lean phenotype. The mass of visceral fat is much less in NRDc−/− compared with wild-type mice (NRDc+/+). While NRDc−/− displayed normal glucose tolerance, serum insulin level was much lower than that of NRDc+/+. NRDc−/− also displayed enhanced insulin sensitivity in insulin tolerance test. Measurement of plasma lipid levels showed no significant difference between NRDc+/+ and NRDc−/− in the total cholesterol content, while the triglyceride is significantly lower in NRDc−/− (57 ± 11 mg/dL) compared with NRDc+/+ (111 ± 5 mg/dL). These data strongly suggested that NRDc is an important regulator of lipid and glucose homeostasis. We next analyzed the heterozygous mutant of NRDc-deficient mice (NRDc+/−). On a normal CHO diet, there were no significant differences between NRDc+/+ and NRDc+/− in body weight, body fat mass, blood glucose, plasma cholesterol and triglyceride. Intriguingly, when challenged with high-fat diet (HFD), NRDc+/− showed significant resistance to HFD-induced obesity, hepatic steatosis and insulin resistance. To clarify the underlying mechanism, we analyzed hepatic gene expression by DNA microarray, and found that many target genes of PPARalpha are upregulated in NRDc−/− liver. We also found nuclear translocation of hepatic NRDc after starvation. These results suggested the functional interaction of NRDc and PPARalpha, which was confirmed by 1) pull-down assay showing the direct binding of NRDc and PPARalpha, 2) luciferase reporter assay showing that NRDc regulates transcriptional activity through PPAR-responsive element (PPRE), and 3) ChIP assay showing that NRDc is recruited to PPRE in the promoter of lipoprotein lipase, a target gene of PPARalpha. In conclusion, NRDc critically controls lipid and glucose metabolism through the modulation of PPARalpha-mediated transcriptional regulation.
- © 2010 by American Heart Association, Inc.