Abstract 1368: A Metalloendopeptidase Nardilysin is an Essential Regulator for Glucose and Lipid Metabolism
Ectodomain shedding is a post-translational modification that releases the extracellular domain of membrane-anchored proteins through proteolysis. We have recently shown that nardilysin (N-arginine dibasic convertase (NRDc)), a metalloendopeptidase of the M16 family, is a potent activator for ectodomain shedding of several membrane proteins, such as membrane-anchored precursor of HB-EGF and TNF-alpha. To clarify the biological roles of NRDc in vivo, we have recently generated NRDc-deficient mice (NRDcKO) by gene targeting. While homozygous mutant of NRDcKO were born at the expected ratio according to Mendel’s law, approximately 80% of them died within 48 hours after birth. The survivors grew up healthily up until two years, but showed obvious growth retardation and lean phenotype. The mass of visceral fat, analyzed by CT scan, is much less in NRDcKO compared with wild-type mice (WT). While NRDcKO displayed normal glucose tolerance, serum insulin level was much lower than that of WT (WT: 154±33 pg/ml, KO: 56±23 pg/ml). NRDcKO also displayed enhanced insulin sensitivity in insulin tolerance test. Measurement of plasma lipid levels showed no significant difference between WT and NRDcKO in the total cholesterol content, while the triglyceride is significantly lower in NRDcKO (57±11 mg/dL) compared with WT (111±5 mg/dL). Analysis of lipoprotein revealed that VLDL fractions are hardly detectable in NRDcKO. Liver mRNA level of lipoprotein lipase (LPL) was remarkably higher in NRDcKO compared to WT. As PPARa is the major regulator of LPL gene expression, these results suggested that PPARa is activated in NRDc-KO. Luciferase reporter assay in vitro showed that NRDc regulates transcriptional activativity through PPAR-responsive element (PPRE). Chromatin immunoprecipitation assay revealed that NRDc is recruited to PPRE in the promotor of LPL, suggesting a direct involvement of NRDc in the transcriptional regulation. Taken together, these results indicated essential roles of NRDc in glucose and lipid metabolisms, and demonstrated a novel function of NRDc as a transcriptional regulator. Most metabolic phenotypes of NRDcKO are just the opposite of those in metabolic syndrome, suggesting that NRDc could be a novel therapeutic target for metabolic syndrome.