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Linagliptin alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis

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Abstract

Non-alcoholic steatohepatitis (NASH) is a primary cause of cirrhosis and hepatocellular carcinoma. Dipeptidyl peptidase (DPP)-4 inhibitors are established therapies for type 2 diabetes and although DPP-4 inhibitors can reduce hepatic steatosis, their impact on local inflammation and fibrosis in NASH remains unknown. Using two different experimental treatment regimens (4- and 2-week treatments) in streptozotocin-treated neonatal mice on a high-fat diet, we show that the DPP-4 inhibitor linagliptin (10 and 30 mg/kg) significantly attenuated the NAS score from 4.9 ± 0.6 to 3.7 ± 0.4 and 3.6 ± 0.3, respectively, in the 4-week study. In the 2-week study, linagliptin 10 mg/kg significantly reduced NAS score from 4.1 ± 0.4 to 2.4 ± 0.4. Telmisartan was used as a positive control in both studies and lowered NAS score to 1.9 ± 0.7 and 1.4 ± 0.3, respectively. Due to streptozotocin treatment, elevated glucose levels were unchanged by either drug treatment. Further, linagliptin 10 mg/kg significantly reduced mRNA levels of SOCS-3 (from 1.68 ± 0.2 to 0.83 ± 0.08), IFN-γ (from 4.0 ± 0.5 to 2.3 ± 0.3), and TNF-α (from 5.7 ± 0.5 to 2.13 ± 0.3). The latter observation was confirmed by immunohistochemistry of TNF-α 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 anti-inflammatory and anti-steatotic activity in NASH.

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Acknowledgments

We 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.

Conflict of interest

Boehringer Ingelheim is the manufacturer of linagliptin. Stelic Institute & Co. is a contract research organisation specialising in animal models of liver-related disease.

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Authors and Affiliations

  1. Boehringer Ingelheim Pharma GmbH & Co. KG, 88397, Biberach an der Riss, Germany

    Thomas Klein, Jan Sandel & Michael Mark

  2. Stelic Institute of Regenerative Medicine, Stelic Institute & Co., 1-9-5 Higashi Azabu, Minato-city, Tokyo, 106-0044, Japan

    Masato Fujii, Yuichiro Shibazaki, Kyoko Wakamatsu & Hiroyuki Yoneyama

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  1. Thomas Klein
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  2. Masato Fujii
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  3. Jan Sandel
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  7. Hiroyuki Yoneyama
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Correspondence to Thomas Klein.

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Klein, T., Fujii, M., Sandel, J. et al. Linagliptin alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis. Med Mol Morphol 47, 137–149 (2014). https://doi.org/10.1007/s00795-013-0053-9

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  • DOI: https://doi.org/10.1007/s00795-013-0053-9

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