Linagliptin alleviates hepatic steatosis and infla

Authors: Thomas Klein Masato Fujii Jan Sandel Yuichiro Shibazaki Kyoko Wakamatsu Michael Mark Hiroyuki Yoneyama

Publish Date: 2013/09/19

Volume: 47, Issue: 3, Pages: 137-149

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Abstract

Nonalcoholic steatohepatitis NASH is a primary cause of cirrhosis and hepatocellular carcinoma Dipeptidyl peptidase DPP4 inhibitors are established therapies for type 2 diabetes and although DPP4 inhibitors can reduce hepatic steatosis their impact on local inflammation and fibrosis in NASH remains unknown Using two different experimental treatment regimens 4 and 2week treatments in streptozotocintreated neonatal mice on a highfat diet we show that the DPP4 inhibitor linagliptin 10 and 30 mg/kg significantly attenuated the NAS score from 49 ± 06 to 37 ± 04 and 36 ± 03 respectively in the 4week study In the 2week study linagliptin 10 mg/kg significantly reduced NAS score from 41 ± 04 to 24 ± 04 Telmisartan was used as a positive control in both studies and lowered NAS score to 19 ± 07 and 14 ± 03 respectively Due to streptozotocin treatment elevated glucose levels were unchanged by either drug treatment Further linagliptin 10 mg/kg significantly reduced mRNA levels of SOCS3 from 168 ± 02 to 083 ± 008 IFNγ from 40 ± 05 to 23 ± 03 and TNFα from 57 ± 05 to 213 ± 03 The latter observation was confirmed by immunohistochemistry of TNFα in liver specimens In addition using microautoradiography we showed that the distribution of radiolabeled linagliptin was heterogeneous with the highest density associated with interlobular bile ducts and portal tracts acini In conclusion these studies confirm that linagliptin has high exposure in hepatic tissue and has both antiinflammatory and antisteatotic activity in NASHWe are grateful to Drs M Sakurai and S Furuuchi for their technical assistance This work was supported by Boehringer Ingelheim The authors were fully responsible for all content and editorial decisions were involved at all stages of manuscript development and have approved the final version Medical writing assistance supported financially by Boehringer Ingelheim was provided by Paul MacCallum of Envision Scientific Solutions during the preparation of this article

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