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 5

In whole liver tissue, immune-related genes and pathways are upregulated in HFHC-fed Dpp4–/– mice but unchanged in Dpp4hep–/– mice.

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In whole liver tissue, immune-related genes and pathways are upregulated...
Pathway scores of immunological pathways in liver tissue of (A) SLD-fed Dpp4+/+ (n = 7) and Dpp4–/– (n = 5) mice, (B) HFHC-fed Dpp4+/+ (n = 11) and Dpp4–/– (n = 6) mice, and (C) HFHC-fed Dpp4GFP (n = 4) and Dpp4hep–/– (n = 11) mice. Log2-normalized mRNA counts of genes associated with (D) inflammasome pathways and (E) NF-κB signaling pathways. Liver mRNA abundance (relative to Actb) of known DPP4 substrates and chemokines/cytokines of (F) Ip-10, (G) Rantes, (H) Mcp-1, and (I) Eotaxin in liver tissue. Log2-normalized mRNA counts of senescence-associated signaling phenotype (SASP) genes in liver tissue of (J) SLD-fed Dpp4+/+ and Dpp4–/– mice, (K) HFHC-fed Dpp4+/+ and Dpp4–/– mice, and (L) HFHC-fed Dpp4GFP and Dpp4hep–/– mice. Liver mRNA abundance (relative to Actb) of SASP genes (M) Ankrd1, (N) Cdkn1a, and (O) Cdkn2a. Box-and-whisker plots: box extends from the 25th to 75th percentiles; the whiskers go down to the smallest value and up to the largest. 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, ***P = 0.0001–0.001, and ****P < 0.0001. nd, not detected.