Merck
  • Home
  • Search Results
  • Linagliptin alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis.

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

Medical molecular morphology (2013-09-21)
Thomas Klein, Masato Fujii, Jan Sandel, Yuichiro Shibazaki, Kyoko Wakamatsu, Michael Mark, Hiroyuki Yoneyama
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
DL-Alanine, ≥99% (HPLC)
Supelco
Hematoxylin
Sigma-Aldrich
Hematoxylin, certified by the Biological Stain Commission
Sigma-Aldrich
DL-Alanine, ≥99%, FCC, FG
Telmisartan, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
DL-Alanine, Vetec, reagent grade, 98%
USP
Telmisartan, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
Telmisartan, ≥98% (HPLC), solid
Alanine, European Pharmacopoeia (EP) Reference Standard
Telmisartan for system suitability, European Pharmacopoeia (EP) Reference Standard
Telmisartan for peak identification, European Pharmacopoeia (EP) Reference Standard