Dipeptidyl peptidase 9 enzymatic activity influences the expression of neonatal metabolic genes

Article ID	Journal	Published Year	Pages	File Type
10903755	Experimental Cell Research	2016	35 Pages	PDF

Abstract

The success of dipeptidyl peptidase 4 (DPP4) inhibition as a type 2 diabetes therapy has encouraged deeper examination of the post-proline DPP enzymes. DPP9 has been implicated in immunoregulation, disease pathogenesis and metabolism. The DPP9 enzyme-inactive (Dpp9 gene knock-in; Dpp9 gki) mouse displays neonatal lethality, suggesting that DPP9 enzyme activity is essential in neonatal development. Here we present gene expression patterns in these Dpp9 gki neonatal mice. Taqman PCR arrays and sequential qPCR assays on neonatal liver and gut revealed differential expression of genes involved in cell growth, innate immunity and metabolic pathways including long-chain-fatty-acid uptake and esterification, long-chain fatty acyl-CoA binding, trafficking and transport into mitochondria, lipoprotein metabolism, adipokine transport and gluconeogenesis in the Dpp9 gki mice compared to wild type. In a liver cell line, Dpp9 knockdown increased AMP-activated protein kinase phosphorylation, which suggests a potential mechanism. DPP9 protein levels in liver cells were altered by treatment with EGF, HGF, insulin or palmitate, suggesting potential natural DPP9 regulators. These gene expression analyses of a mouse strain deficient in DPP9 enzyme activity show, for the first time, that DPP9 enzyme activity regulates metabolic pathways in neonatal liver and gut.

Keywords

ACADM ΔΔCt HNF-4α diacylglycerol acyltransferase 1 DGAT1 IGFBP1 SREBP-1 GKO SCD1 comparative Ct AMPK G6PC ChREBP HGF VEGF-A IκBα GKI GLUT4 DPP9 3-hydroxy-3-methylglutaryl-CoA synthase peroxisome proliferator-activated receptor γ coactivator-1α acetyl-coenzyme A carboxylase alpha MCFAs acyl-CoA synthetase long-chain family member 1 ACSL1 Very long chain acyl-CoA dehydrogenase Phosphatidylinositol-3-kinases CXCL10 FABP2 PDK4 FATP4 ACADVL LCFAs AK2 C-X-C motif chemokine 10 HMGCS2 PEPCK DPP SUMO HDL ADIPOR2 DMEM EGF FOXO1 ACC PPARα PI3K IRS IL-1β HMG-CoA IL-1RA FAP PGC-1α EGFR 3-Hydroxy-3-methylglutaryl-CoA AMP-activated protein kinase high-density lipoprotein HET Dulbecco's modified Eagle's medium VLDLR interleukin-1 receptor antagonist Akt Stearoyl-coenzyme A desaturase 1 fatty acid synthase Long-chain fatty acids Medium-chain fatty acids insulin receptor substrate tumour necrosis factor α Forkhead box O1 glucose transporter 4 dipeptidyl peptidase Medium chain acyl-CoA dehydrogenase epidermal growth factor Hepatocyte growth factor sterol regulatory element binding transcription factor 1 cytoplasmic extract nuclear extract non-targeting vascular endothelial growth factor-A TNF-α Fasn phosphoenolpyruvate carboxykinase Endothelial lipase Gene knock-out wild type heterozygote pop Fibroblast activation protein Insulin-like growth factor-binding protein 1 protein kinase B prolyl oligopeptidase Pyruvate dehydrogenase kinase 4 carnitine palmitoyltransferase 1a small ubiquitin-like modifier glucose 6-phosphatase adiponectin receptor 2 Epidermal growth factor receptor Very low-density lipoprotein receptor Peroxisome proliferator activated receptor α glucocorticoid receptor