The Dipeptidyl Peptidase-4 Inhibitor Teneligliptin Attenuates Hepatic Lipogenesis via AMPK Activation in Non-Alcoholic Fatty Liver Disease Model Mice.

Abstract

Non-alcoholic fatty liver disease (NAFLD), which is strongly associated with metabolic syndrome, is increasingly a major cause of hepatic disorder. Dipeptidyl peptidase (DPP)-4 inhibitors, anti-diabetic agents, are expected to be effective for the treatment of NAFLD. In the present study, we established a novel NAFLD model mouse using monosodium glutamate (MSG) and a high-fat diet (HFD) and investigated the effects of a DPP-4 inhibitor, teneligliptin, on the progression of NAFLD. Male MSG/HFD-treated mice were divided into two groups, one of which received teneligliptin in drinking water. Administration of MSG and HFD caused mice to develop severe fatty changes in the liver, but teneligliptin treatment improved hepatic steatosis and inflammation, as evaluated by the NAFLD activity score. Serum alanine aminotransferase and intrahepatic triglyceride levels were significantly decreased in teneligliptin-treated mice (p < 0.05). Hepatic mRNA levels of the genes involved in de novo lipogenesis were significantly downregulated by teneligliptin (p < 0.05). Moreover, teneligliptin increased hepatic expression levels of phosphorylated AMP-activated protein kinase (AMPK) protein. These findings suggest that teneligliptin attenuates lipogenesis in the liver by activating AMPK and downregulating the expression of genes involved in lipogenesis. DPP-4 inhibitors may be effective for the treatment of NAFLD and may be able to prevent its progression to non-alcoholic steatohepatitis.

• Authors: Takayasu Ideta, Yohei Shirakami, Tsuneyuki Miyazaki, Takahiro Kochi, Hiroyasu Sakai, Hisataka Moriwaki, Masahito Shimizu
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 16 Issue 12 Pg. 29207-18 (Dec 08 2015) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 26670228 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl)thiazolidine
• Biomarkers
• Dipeptidyl-Peptidase IV Inhibitors
• Pyrazoles
• Thiazolidines
• Triglycerides
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Biomarkers
• Dipeptidyl-Peptidase IV Inhibitors (pharmacology)
• Disease Models, Animal
• Enzyme Activation (drug effects)
• Lipid Metabolism
• Liver (drug effects, metabolism, pathology)
• Male
• Mice
• Non-alcoholic Fatty Liver Disease (drug therapy, etiology, metabolism, pathology)
• Phosphorylation
• Pyrazoles (pharmacology)
• Signal Transduction
• Thiazolidines (pharmacology)
• Triglycerides (metabolism)