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
View: Text | PDF
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

×

Figure 4

Fibrosis-related genes are upregulated in HFHC-fed Dpp4–/– but not Dpp4hep–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
Fibrosis-related genes are upregulated in HFHC-fed Dpp4–/– but not Dpp4h...
(A) Alanine aminotransferase (ALT), (B) aspartate transaminase (AST), and (C) alkaline phosphatase (ALP). Liver mRNA abundance (relative to Actb) of (D) Col1a1, (E) Col3a1, (F) Mmp2, (G) Mmp11, (H) Des, and (I) Ddr2. Representative images of liver stained with Picrosirius red (PSR) and quantitation of red-stained pixels in (J) SLD-fed Dpp4+/+ (n = 6–7) and Dpp4–/– (n = 5–6) mice, (K) HFHC-fed Dpp4+/+ (n = 9–11) and Dpp4–/– (n = 6) mice, and (L) HFHC-fed Dpp4GFP (n = 4) and Dpp4hep–/– (n = 11–12) mice (scale bar: 250 μm) and (M) quantitation of red-stained pixels. (N) Liver METAVIR score prevalence. Data are presented as the means ± SEM, analyzed by unpaired Student’s t test with Welch’s correction; *P = 0.01–0.05, **P = 0.001–0.01, and ***P = 0.0001–0.001.