Dipeptidyl Peptidase-4 in Cariometabolic Disease

Abstract

The cardiovascular implications of modulating cell specific expression of the serine protease dipeptidyl peptidase-4 (DPP4) were investigated in a series of murine models of metabolic dysfunction-associated steatotic liver disease (MASLD), cardiometabolic disease and myocardial infarction. In vivo experiments were conducted using several genetic models, including systemic Dpp4 knockout mice (Dpp4-/-), hepatocyte-specific knockout mice (Dpp4hep-/-) and endothelial cell-specific knockout mice (Dpp4EC-/-), which were challenged with high-fat, high cholesterol (HFHC) feeding, to induce MASLD and heart failure (HF), and exacerbate surgical myocardial infarction (MI). Pharmaceutical modulation of DPP4 was also performed by adding the DPP4 inhibitor (DPP4i) sitagliptin, and/or metformin, to drinking water. Molecular studies were then performed to evaluate the role of DPP4 in hepatic steatosis, hepatic glucose production (HGP), inflammation and fibrosis, together with echocardiography to evaluate cardiac function. Genetic ablation of hepatocyte-derived DPP4 increased incretin hormone bioactivity in the portal vein, which was associated with reduced HGP. Liver fibrosis and gene expression of immune-related pathways were increased in aged, obese Dpp4-/- mice, however liver steatosis and plasma lipids were unchanged. Conversely, expression of immune-related pathways was unchanged in Dpp4hep-/- mice. Additionally, in a lean model of MASLD, DPP4 activity increased, dissociating its enzymatic activity from obesity, while DPP4 protein decreased with viral clearance in patients with HCV treated with antiviral drugs. Within the heart of HFHC-diet fed aged mice, immune-related pathways in Dpp4hep-/- were reduced in ventricular tissue. Despite these molecular changes in the heart, there were no functional changes in systolic and diastolic parameters. Lastly, Dpp4-/-, Dpp4hep-/- and Dpp4EC-/- mice were treated with sitagliptin, metformin or a combination of these drugs (dual therapy) to investigate the clinical cardioprotective outcomes. Four weeks after left anterior descending (LAD) coronary artery-ligation, cardiac function demonstrated via left ventricular ejection fraction (LVEF) was significantly increased in Dpp4hep-/- mice compared to controls with dual therapy treatment, both pre- and post-MI. This was not associated with a higher prevalence of fully kinetic myocardia, however Dpp4EC-/- mice did indeed have more fully kinetic hearts without changes in LVEF. Evaluating DPP4 activity and protein over time revealed a dissociated relationship between these measurements, where activity decreased 7 days after infarct, while protein continued to rise until endpoint. Overall, this thesis highlights the complexity of DPP4 biology in multiple diseases, and its utility as a therapeutic target.