ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 63 GP200 | DOI: 10.1530/endoabs.63.GP200

A liver selective knockdown of Dpp4 by therapeutic siRNA affects lipid metabolism but fails to improve glucose control in diabetic mice

Sven Wolfgang Görgens, Kerstin Jahn-Hofmann, Christiane Metz-Weidmann, Uwe Schwahn, Paulus Wohlfart, Matthias Schäfer & Maximilian Bielohuby

Sanofi-Aventis Deutschland GmbH, R&D, Industriepark Hoechst, Frankfurt, Germany.

Objective: The exopeptidase dipeptidyl peptidase 4 (Dpp4) selectively cleaves N-terminal dipeptides from several substrates, including cytokines, growth factors, neuropeptides, and the incretin hormones. The systemic inhibition of Dpp4 by the so-called gliptins (oral Dpp4 inhibitors) represents an effective and established treatment option for type 2 diabetes (T2D). In the current study we investigated in healthy as well as in obese and diabetic mice if a liver selective knock-down of Dpp4 by therapeutic siRNAs could be a novel, similarly effective treatment option for T2D. Liver selective inhibition of Dpp4 by therapeutic siRNAs could potentially reduce unwanted side effects which are induced by systemic inhibition and has the potential to exert a sustained, long-lasting effect compared to the established daily oral treatment regimen. Furthermore, effects on hepatic steatosis, inflammation and lipid metabolism were analyzed in mice after hepatoselective Dpp4 knock-down.

Methods: The knock-down efficacy and IC50 values of siRNAs targeting Dpp4 were analyzed in PC3 cells. Diabetic db/db, respective lean controls and lean C57BL/6J mice were injected intravenously with a liposomal formulation of siRNAs targeting Dpp4 (3 injections during 13 days for C57BL/6 mice and 5 injections during 30 days for db/db mice). Mice were metabolically characterized by standard procedures approx. 2 weeks after knockdown of Dpp4. Additional mice were treated with an oral Dpp4 inhibitor as a positive control.

Results: In both mouse models we observed a robust knock-down ~75% of hepatic Dpp4. As expected, the systemic inhibition of the enzymatic Dpp4 activity by an oral inhibitor significantly improved glucose handling and reduced circulating IL-6 levels in diabetic animals. In contrast, the reduction of hepatic Dpp4 production via therapeutic siRNAs does not affect circulating active GLP-1/GIP levels and consequently also no modulation of glucose metabolism was observed in mice (as demonstrated by oGTT and fasting glucose and insulin concentrations). Furthermore, treated db/db mice did not display significant improvements of hepatic steatosis. However, circulating cholesterol and hepatic mRNA expression of genes involved in lipid metabolism, namely Acaca, Scd1, Fasn and Pparg were significantly reduced after Dpp4 siRNA treatment.

Conclusion: These results point out that the major source for circulating Dpp4 is probably not the liver and therefore hepatic Dpp4 silencing seems to be not an appropriate tool for the treatment of T2D. However, hepatocyte-derived Dpp4 regulates liver lipid metabolism, potentially though paracrine mechanisms. Thus, targeting this pathway may have benefits that are distinct from those observed with systemic oral Dpp4 inhibitors.

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