A siRNA mediated hepatic dpp4 knockdown affects lipid, but not glucose metabolism in diabetic mice

Autoři: Sven Wolfgang Görgens aff001;  Kerstin Jahn-Hofmann aff001;  Dinesh Bangari aff002;  Sheila Cummings aff002;  Christiane Metz-Weidmann aff001;  Uwe Schwahn aff001;  Paulus Wohlfart aff001;  Matthias Schäfer aff001;  Maximilian Bielohuby aff001
Působiště autorů: Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, Frankfurt am Main, Germany aff001;  Sanofi, Global Discovery Pathology, Translational In-vivo Models Framingham, MA, United States of America aff002
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0225835


Systemic inhibition of dipeptidyl peptidase 4 (dpp4) represents an effective and established treatment option for type 2 diabetes (T2D). The current study investigated in mice if a liver selective knock-down of dpp4 by therapeutic siRNAs could be a novel, similarly effective treatment option for T2D. Furthermore, the potential effects on hepatic steatosis, inflammation and lipid metabolism were investigated after hepato-selective knock-down of dpp4. The knock-down efficiency and IC50 values of siRNAs targeting dpp4 were analyzed in PC3 cells. In two independent studies, either db/db mice or C57BL/6J mice were injected intravenously with a liposomal formulation of siRNAs targeting either dpp4 or a non-targeting control, followed by metabolically characterization. In comparator groups, additional cohorts of mice were treated with an oral dpp4 inhibitor. In both animal studies, we observed a robust knock-down (~75%) of hepatic dpp4 with a potent siRNA. Hepatic dpp4 knockdown did not significantly affect glucose metabolism or circulating incretin concentrations in both animal studies. However, in obese and diabetic db/db mice hepatic steatosis was reduced and hepatic mRNA expression of acaca, scd1, fasn and pparg was significantly lower after siRNA treatment. Systemic inhibition of the enzymatic dpp4 activity by an oral dpp4 inhibitor significantly improved glucose handling in db/db mice but did not affect hepatic endpoints. These data demonstrate that a targeted reduction of dpp4 expression in the liver may not be sufficient to improve whole-body glucose metabolism in obese and diabetic mice but may improve hepatic lipid metabolism.

Klíčová slova:

Fatty liver – Glucose metabolism – Inflammation – Mouse models – Obesity – Oral glucose suppression test – Small interfering RNAs – Steatosis


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2019 Číslo 12
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