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

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.

Preservation of Glucagon-Like Peptide-1 Level Attenuates Angiotensin II-Induced Tissue Fibrosis by Altering AT1/AT2 Receptor Expression and Angiotensin-Converting Enzyme 2 Activity in Rat Heart

“…Although we did not measure plasma levels of GLP-1 and blood sugar, the doses selected for liraglutide and linagliptin are primarily based on previous observations showing that the GLP-1 level is maintained and glucose is controlled with these drugs [41][42][43][44]. In review of the present results, liraglutide or linagliptin is a potent protector against Ang II-induced cardiac fibrosis by providing exogenous GLP-1 or preserving endogenous GLP-1.…”

GLP-1 based therapies: clinical implications for gastroenterologists

“…GLP-1-induced improvement of hepatic triglyceride handling probably also plays a role. Furthermore, GLP-1RAs and DPP-4Is reduce hepatocyte endoplasmic reticulum stress163 164 and inflammatory cytokines,164 165 both involved in NASH development.…”

Linagliptin inhibits lipopolysaccharide-stimulated interleukin-6 production, intranuclear p65 expression, and p38 mitogen-activated protein kinase phosphorylation in human umbilical vein endothelial cells

“…The anti-inflammatory effects of linagliptin have been elucidated in vivo [14,[27][28][29][30]. However, to the best of our knowledge, no study has examined these effects in vitro.…”