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Hepatocyte-derived DPP4 regulates portal GLP-1 bioactivity, modulates glucose production, and when absent influences

Natasha A Trzaskalski1,2, Branka Vulesevic1,2, My-Anh Nguyen1,2

  • 1Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ontario, Canada.

JCI Insight
|December 6, 2022
PubMed

Insights

Dipeptidyl peptidase-4 (DPP4) in liver cells regulates gluconeogenesis. Complete DPP4 absence in mice accelerates liver fibrosis, indicating complex roles beyond metabolic syndrome and highlighting its significance in liver disease progression.

Area of Science:

  • Biochemistry
  • Hepatology
  • Metabolic Diseases

Background:

  • Elevated circulating dipeptidyl peptidase-4 (DPP4) is a known liver disease biomarker.
  • The specific roles of DPP4 in gluconeogenesis and metabolic-associated fatty liver disease (MAFLD) progression are not fully understood.

Purpose of the Study:

  • To investigate the role of DPP4 in regulating incretin hormone bioactivity and gluconeogenesis within hepatocytes.
  • To determine the impact of DPP4 deficiency on liver fibrosis, steatosis, and dyslipidemia in aged mice with metabolic syndrome.
  • To explore the relationship between DPP4 expression, immune signaling, and liver disease in various mouse models and human patients.

Main Methods:

  • Utilized Dpp4-/- mice and wild-type littermates, subjected to high-fat, high-cholesterol diets.
  • Analyzed liver transcripts to identify enriched biological pathways in Dpp4-/- mice.
  • Examined DPP4 expression in F4/80+ cells under specific dietary conditions.
  • Investigated DPP4 levels in lean mouse models of nonalcoholic fatty liver disease (NAFLD).
  • Assessed DPP4 protein and activity levels in hepatitis C patients undergoing direct antiviral therapy.

Main Results:

  • Hepatocyte DPP4, not endothelial DPP4, regulates incretin hormones and gluconeogenesis.
  • Complete DPP4 absence in aged mice with metabolic syndrome accelerated liver fibrosis, without affecting dyslipidemia or steatosis.
  • Liver transcripts in Dpp4-/- mice showed enrichment in inflammasome, p53, and senescence pathways.
  • High-fat, high-cholesterol feeding reduced Dpp4 expression in F4/80+ cells with minimal immune signaling changes.
  • A lean mouse model of severe NAFLD exhibited a 4-fold increase in circulating DPP4.
  • In hepatitis C patients, DPP4 levels decreased with viral clearance, but metabolic factors did not improve.

Conclusions:

  • Hepatocyte DPP4 plays a critical role in regulating gluconeogenesis and incretin bioactivity.
  • DPP4 deficiency exacerbates liver fibrosis in metabolic syndrome, suggesting a protective role in this context.
  • Circulating DPP4 elevations in hepatitis C are not primarily driven by metabolic disturbances.
  • DPP4's complex role in liver disease warrants further investigation, particularly concerning fibrosis and inflammation.
Keywords:
FibrosisGluconeogenesisInflammationMetabolismPeptides

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