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

Baumeier, Christian; Schlüter, Luisa; Saussenthaler, Sophie; Laeger, Thomas; Rödiger, Maria; Alaze, Stella Amelie; Fritsche, Louise; Häring, Hans-Ulrich; Stefan, Norbert; Fritsche, Andreas; Schwenk, Robert Wolfgang; Schürmann, Annette

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive deposition of fat (steatosis) in the liver and can be classified into two major clinical-histological subgroups: (i) non-alcoholic fatty liver (NAFL) and (ii) non-alcoholic steatohepatitis (NASH). The prevalence of NAFLD in the general adult population ranges from 25% to 45% and rises with increasing incidence of obesity and type 2 diabetes [1] . Patients with NASH reveal augmented mortality rate, whereas NAFL has been linked to an increased risk of type 2 diabetes [2] . Current management for NAFLD includes lifestyle modifications, control of metabolic risk factors, and pharmacological therapies. However, since only biopsyproven NASH patients receive medical treatment [3] , there is a need for suitable drugs for the treatment of NAFL. Dipeptidyl peptidase 4 (DPP4) could serve as target in NAFL therapy. DPP4 is a serine protease that cleaves a variety of substrates including incretin hormones, chemokines, growth factors, and neuropeptides [4] . It is ubiquitously expressed on the apical surface of many cell types and also occurs as a soluble form (sDPP4) in the circulation and other body fluids [5, 6] . There is accumulating evidence that DPP4 is involved in the development of chronic liver disease [5, 7, 8] . DPP4 is highly expressed in the liver, and its expression as well as circulating levels are increased in NAFL and NASH [8e10] . sDPP4 is suggested as biomarker of NAFLD [11] and was shown to be a valid measure for hepatocyte apoptosis and fibrosis [12] . Genetic ablation of Dpp4 in mice [13] and rats [14] results in improved insulin sensitivity and liver function, and pharmacological inhibition of DPP4 causes reduction of hepatic steatosis and improvement of insulin sensitivity in mouse models of obesity [15, 16] and diabetes [17] . Beside its role in the degradation of incretin hormones, DPP4 was shown to exert incretin-independent functions such as the induction of insulin resistance [18e21] and inflammation [22] in different cellular systems. However, whether elevated DPP4 and in particular hepatic DPP4 triggers insulin resistance and NAFLD or simply reflects the state of liver disease is not entirely clarified. We recently demonstrated in diet-induced obesity mice that expression and release of DPP4 is substantially increased in liver when compared to adipose depots [23] . We further showed that elevated expression of Dpp4 in livers of 6-week-old mice associates with early insulin resistance, which, in turn, triggers later liver steatosis [23] . In the current study, we analyzed the DPP4 activity in plasma of healthy and NAFLD subjects and elucidated the effect of hepatocyte-specific Dpp4 overexpression on the development of insulin resistance and liver steatosis in mice under obese conditions.