Hepatocyte-derived DPP4 regulates portal GLP-1 bioactivity, modulates glucose production, and when absent influences NAFLD progression
Natasha A. Trzaskalski, Branka Vulesevic, My-Anh Nguyen, Natasha Jeraj, Evgenia Fadzeyeva, Nadya M. Morrow, Cassandra A.A. Locatelli, Nicole Travis, Antonio A. Hanson, Julia R.C. Nunes, Conor O’Dwyer, Jelske N. van der Veen, Ilka Lorenzen-Schmidt, Rick Seymour, Serena M. Pulente, Andrew C. Clément, Angela M. Crawley, René L. Jacobs, Mary-Anne Doyle, Curtis L. Cooper, Kyoung-Han Kim, Morgan D. Fullerton, Erin E. Mulvihill
Natasha A. Trzaskalski, Branka Vulesevic, My-Anh Nguyen, Natasha Jeraj, Evgenia Fadzeyeva, Nadya M. Morrow, Cassandra A.A. Locatelli, Nicole Travis, Antonio A. Hanson, Julia R.C. Nunes, Conor O’Dwyer, Jelske N. van der Veen, Ilka Lorenzen-Schmidt, Rick Seymour, Serena M. Pulente, Andrew C. Clément, Angela M. Crawley, René L. Jacobs, Mary-Anne Doyle, Curtis L. Cooper, Kyoung-Han Kim, Morgan D. Fullerton, Erin E. Mulvihill
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Research Article Inflammation Metabolism

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

Abstract

Elevated circulating dipeptidyl peptidase-4 (DPP4) is a biomarker for liver disease, but its involvement in gluconeogenesis and metabolic associated fatty liver disease progression remains unclear. Here, we identified that DPP4 in hepatocytes but not TEK receptor tyrosine kinase–positive endothelial cells regulates the local bioactivity of incretin hormones and gluconeogenesis. However, the complete absence of DPP4 (Dpp4–/–) in aged mice with metabolic syndrome accelerates liver fibrosis without altering dyslipidemia and steatosis. Analysis of transcripts from the livers of Dpp4–/– mice displayed enrichment for inflammasome, p53, and senescence programs compared with littermate controls. High-fat, high-cholesterol feeding decreased Dpp4 expression in F4/80+ cells, with only minor changes in immune signaling. Moreover, in a lean mouse model of severe nonalcoholic fatty liver disease, phosphatidylethanolamine N-methyltransferase mice, we observed a 4-fold increase in circulating DPP4, in contrast with previous findings connecting DPP4 release and obesity. Last, we evaluated DPP4 levels in patients with hepatitis C infection with dysglycemia (Homeostatic Model Assessment of Insulin Resistance > 2) who underwent direct antiviral treatment (with/without ribavirin). DPP4 protein levels decreased with viral clearance; DPP4 activity levels were reduced at long-term follow-up in ribavirin-treated patients; but metabolic factors did not improve. These data suggest elevations in DPP4 during hepatitis C infection are not primarily regulated by metabolic disturbances.

Authors

Natasha A. Trzaskalski, Branka Vulesevic, My-Anh Nguyen, Natasha Jeraj, Evgenia Fadzeyeva, Nadya M. Morrow, Cassandra A.A. Locatelli, Nicole Travis, Antonio A. Hanson, Julia R.C. Nunes, Conor O’Dwyer, Jelske N. van der Veen, Ilka Lorenzen-Schmidt, Rick Seymour, Serena M. Pulente, Andrew C. Clément, Angela M. Crawley, René L. Jacobs, Mary-Anne Doyle, Curtis L. Cooper, Kyoung-Han Kim, Morgan D. Fullerton, Erin E. Mulvihill

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Figure 1

HGP is decreased in HFHC-fed Dpp4–/– and hepatocyte-specific Dpp4-knockout mice.

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HGP is decreased in HFHC-fed Dpp4–/– and hepatocyte-specific Dpp4-knocko...
(A) Time course of glucose infusion rates (GIRs) and plasma glucose and endpoint GIR during hyperinsulinemic-euglycemic clamp of Dpp4+/+ (n = 6) and Dpp4–/– (n = 5) mice. (B) Glucose disposal rate (GDR), (C) basal and clamp HGP, and (D) percentage of HGP suppression under clamp conditions. Hepatic mRNA abundance (relative to Actb) for genes associated with (E) hepatic gluconeogenesis (Gck, G6p, Pck, Gsk3β, and Pygl) and (F) insulin signaling (Gcgr, Igf1, and Igf1r) in Dpp4+/+ (n = 11) and Dpp4–/– (n = 7) mice. Gck, glucokinase; G6p, glucose-6-phosphatase; Pck, phosphoenolpyruvate carboxykinase; Gsk3β, glycogen synthase kinase 3β; Pygl, glycogen phosphorylase; Gcgr, glucagon receptor; Igf1, insulin-like growth factor 1; Igf1r, Igf1 receptor. (G) Time course of plasma glucose and glucose infusion rates, and endpoint GIR during hyperinsulinemic-euglycemic clamp of Dpp4GFP (n = 4) and Dpp4hep–/– (n = 5) mice. (H) GDR, (I) basal and clamp HGP, and (J) percentage of HGP suppression under clamp conditions. Hepatic mRNA abundance (relative to Actb) for genes associated with (K) hepatic gluconeogenesis (Gck, G6p, Pck, Gsk3β, and Pygl) and (L) insulin signaling (Gcgr, Igf, and Igf1r) in Dpp4GFP (n = 4) and Dpp4hep–/– (n = 11) mice. Data are presented as the mean ± SEM. Time-course data are analyzed by 2-way ANOVA with Tukey’s multiple comparisons post hoc test; remaining data analyzed by unpaired Student’s t test with Welch’s correction, *P = 0.01–0.05, **P = 0.001–0.01.