Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease

Abstract

ObjectiveIncreased hepatic expression of dipeptidyl peptidase 4 (DPP4) is associated with non-alcoholic fatty liver disease (NAFLD). Whether this is causative for the development of NAFLD is not yet clarified. Here we investigate the effect of hepatic DPP4 overexpression on the development of liver steatosis in a mouse model of diet-induced obesity.MethodsPlasma DPP4 activity of subjects with or without NAFLD was analyzed. Wild-type (WT) and liver-specific Dpp4 transgenic mice (Dpp4-Liv-Tg) were fed a high-fat diet and characterized for body weight, body composition, hepatic fat content and insulin sensitivity. In vitro experiments on HepG2 cells and primary mouse hepatocytes were conducted to validate cell autonomous effects of DPP4 on lipid storage and insulin sensitivity.ResultsSubjects suffering from insulin resistance and NAFLD show an increased plasma DPP4 activity when compared to healthy controls. Analysis of Dpp4-Liv-Tg mice revealed elevated systemic DPP4 activity and diminished active GLP-1 levels. They furthermore show increased body weight, fat mass, adipose tissue inflammation, hepatic steatosis, liver damage and hypercholesterolemia. These effects were accompanied by increased expression of PPARγ and CD36 as well as severe insulin resistance in the liver. In agreement, treatment of HepG2 cells and primary hepatocytes with physiological concentrations of DPP4 resulted in impaired insulin sensitivity independent of lipid content.ConclusionsOur results give evidence that elevated expression of DPP4 in the liver promotes NAFLD and insulin resistance. This is linked to reduced levels of active GLP-1, but also to auto- and paracrine effects of DPP4 on hepatic insulin signaling.

Plasma proteome profiling discovers novel proteins associated with non‐alcoholic fatty liver disease

“…Studies have shown that increased hepatic expression of DPP4 is associated with NAFLD (Balaban et al , ; Miyazaki et al , ; Itou et al , ). Hepatocyte‐specific DPP4 overexpression in mice increases body fat and promotes hepatic steatosis, suggesting that this association is causative (Baumeier et al , ). Taken together with our proteome profiling results, levels of soluble DPP4 in plasma may represent an even stronger candidate as an indicator of liver damage.…”

Impact of dapagliflozin, an SGLT2 inhibitor, on serum levels of soluble dipeptidyl peptidase‐4 in patients with type 2 diabetes and non‐alcoholic fatty liver disease

“…In a recent study, liver-specific DPP-4 transgenic mice showed elevation of systemic DPP-4 enzyme activity, hypercholesterolaemia and an increased adipose fat mass with inflammation and hepatic steatosis, suggesting that increased expression of DPP-4 in the liver not only promotes NAFLD but also contributes to hepatic insulin resistance. 20 A very recent study demonstrated that obesity stimulates the production and secretion of soluble DPP-4 by hepatocytes, which promotes adipose tissue inflammation and insulin resistance in the liver via caveolin-1, suggesting that sDPP-4 may be involved in crosstalk between the liver and adipose tissue as a hepatokine. 11 However, inhibition of circulating DPP-4 enzyme activity by sitagliptin (a DPP-4 inhibitor) did not block adipose tissue inflammation or improve hepatic insulin resistance.…”

Significance of circulatory DPP4 activity in metabolic diseases

“…Mouse genetic experiments have also provided evidence for liver derived DPP4 as an important contributor to circulating soluble pool. For example, hepatic overexpression of DPP4 showed positive correlation with ex vivo liver DPP4 release as well as plasma DPP4 activity . Moreover, release of DPP4 is higher in liver explants of high gainer mice compared to low gainer.…”