Non-enzymatic role of dipeptidyl peptidase-4 in regulating adenosine 2A receptor in MAFLD

Abstract

Non-catalytic function of dipeptidyl peptidase-4 (DPP4) plays a crucial role in inflammation and immune regulation in the body; however, its significance in metabolic associated fatty liver disease (MAFLD) remains largely unknown. We sought to examine the effects of Dpp4 disruption on aspects of MAFLD and to elucidate underlying mechanisms. Wild-type (WT), Dpp4-disrupted, and DPP4 inhibitor-treated C57BL/6J male mice were fed a high-fat diet (HFD) for 12 weeks to establish MAFLD. Hepatic steatosis and liver proinflammatory responses were assessed. Furthermore, bone marrow-derived macrophages from different genotypes were co-cultured with mouse hepatocytes to assess their roles in inflammatory and metabolic responses in vitro. Upon HFD feeding, Dpp4-disrupted mice exhibited significantly attenuated hepatic steatosis and inflammation compared to both DPP4 inhibitor-treated and control WT mice. In vitro, Dpp4-deficient macrophages demonstrated a reduced proinflammatory phenotype. Consequently, these macrophages elicited less fat deposition in co-cultured wild-type hepatocytes. Mechanistically, Dpp4 deficiency significantly upregulated the protein abundance of the adenosine 2A receptor (A2AR) while markedly reducing adenosine deaminase (ADA) levels in both liver tissues and bone marrow-derived macrophages. Our results demonstrate that genetic disruption of Dpp4, unlike its pharmacological inhibition, ameliorates MAFLD progression. This protective effect is mediated through a novel non-catalytic mechanism involving the upregulation of A2AR and downregulation of ADA, which collectively inhibit macrophage-driven inflammation.