Dipeptidyl peptidase-4 impairs insulin signaling and promotes lipid accumulation in hepatocytes

作者：Rufinatscha Kerstin; Radlinger Bernhard; Dobner Jochen; Folie Sabrina; Bon Claudia; Profanter Elisabeth; Ress Claudia; Salzmann Karin; Staudacher Gabriele; Tilg Herbert; Kaser Susanne

来源：Biochemical and Biophysical Research Communications, 2017, 485(2): 366-371.

DOI：10.1016/j.bbrc.2017.02.071

• DPP4
• Liver
• Insulin signaling
• Lipid metabolism
• Insulin resistance

Dipeptidyl-peptidase 4 [DPP-4) has evolved into an important target in diabetes therapy due to its role in incretin hormone metabolism. In contrast to its systemic effects, cellular functions of membranous DPP-4 are less clear. Here we studied the role of DPP-4 in hepatic energy metabolism.
In order to distinguish systemic from cellular effects we established a cell culture model of DPP-4 knockdown in human hepatoma cell line HepG2.
DPP-4 suppression was associated with increased basal glycogen content due to enhanced insulin signaling as shown by increased phosphorylation of insulin-receptor substrate 1 (IRS-1), protein kinase B/Akt and mitogen-activated protein kinases (MAPK)/ERK, respectively. Additionally, glucose-6-phosphatase cDNA expression was significantly decreased in DPP-4 deficiency. Reduced triglyceride content in DPP-4 knockdown cells was paralleled by enhanced expressions of peroxisome proliferator-activated receptor alpha (PPARa) and carnitine palmitoyltransferase 1 (CPT-1) while sterol regulatory element-binding protein lc (SREBP-1c) expression was significantly decreased.
Our data suggest that hepatic DPP-4 induces a selective pathway of insulin resistance with reduced glycogen storage, enhanced glucose output and increased lipid accumulation in the liver. Hepatic DPP-4 might be a novel target in fatty liver disease in patients with glucose intolerance.

• 出版日期2017-4-1