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01-09-2014 | Original Paper

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

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

Published in: Medical Molecular Morphology | Issue 3/2014

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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Title: Linagliptin alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis
Authors: Thomas Klein
Masato Fujii
Jan Sandel
Yuichiro Shibazaki
Kyoko Wakamatsu
Michael Mark
Hiroyuki Yoneyama
Publication date: 01-09-2014
Publisher: Springer Japan
Published in: Medical Molecular Morphology / Issue 3/2014
Print ISSN: 1860-1480
Electronic ISSN: 1860-1499
DOI: https://doi.org/10.1007/s00795-013-0053-9

2024 ASCO Annual Meeting

Springer Medicine

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

Abstract

2024 ASCO Annual Meeting

Springer Medicine

Abstract

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