Elevated hepatic DPP4 causes fatty liver and insulin resistance

Background/Aims:

Recent data indicate that hepatic expression of dipeptidyl peptidase 4 (DPP4) is associated with the development of non-alcoholic fatty liver disease (NAFLD). Here, we investigated the effect of liver specific Dpp4 overexpression on the development of hepatosteatosis and insulin resistance, and tested if NAFLD patients show a systemic increase of DPP4.

Methods:

Transgenic mice with a liver specific overexpression of Dpp4 (DPP4-TG) were fed a high-fat diet and characterized for body weight, body composition, hepatic fat content and insulin sensitivity. To validate cell autonomous effects of DPP4, in vitro experiments were performed. Furthermore, plasma of human subjects with or without NAFLD was analyzed for DPP4 activity.

Results:

Mice with a constitutive Dpp4 overexpression in the liver showed an increased body weight development which was attributed to an elevated fat mass. Moreover, these animals developed hepatosteatosis and hypercholesterolemia in comparison to their wild-type littermates. Plasma DPP4 activity was increased which was accompanied by a reduction of GLP-1. DPP4-TG mice revealed a defective insulin signaling shown by an impaired insulin tolerance and insulin stimulated Akt phosphorylation in liver and adipose tissue. Moreover, treatment of HepG2 cells and primary mouse hepatocytes with recombinant DPP4 resulted in an impaired insulin signaling. Finally, NAFLD patients showed significantly elevated plasma DPP4 activities when compared to controls without hepatosteatosis.

Conclusion:

Our data show a direct connection between elevated hepatic DPP4 and the development of NAFLD. This might be linked to the reduction of systemic GLP-1, but also to direct effects of DPP4 on hepatic insulin signaling.