Linagliptin Ameliorates Hepatic Steatosis via Non-Canonical Mechanisms in Mice Treated with a Dual Inhibitor of Insulin Receptor and IGF-1 Receptor

• Published in: International journal of molecular sciences 2020-10, Vol.21 (21), p.7815
• Main Authors: Okuyama, Tomoko, Shirakawa, Jun, Tajima, Kazuki, Ino, Yoko, Vethe, Heidrun, Togashi, Yu, Kyohara, Mayu, Inoue, Ryota, Miyashita, Daisuke, Li, Jinghe, Goto, Nozomi, Ichikawa, Taiga, Yamasaki, Shingo, Ohnuma, Haruka, Takayanagi, Rie, Kimura, Yayoi, Hirano, Hisashi, Terauchi, Yasuo
• Format: Article
• Language: English
• Subjects: Animals; Aryl Hydrocarbon Hydroxylases - metabolism; Atrophy; Blood Glucose - metabolism; Cytochrome; Cytochrome P450; Cytochrome P450 Family 2 - metabolism; Cytochromes P450; Diabetes; DPP-4 inhibitors; Drug dosages; Enzymes; Fatty liver; Gene expression; Gene Expression Regulation - drug effects; Gluconeogenesis; Glucose; Glucose tolerance; hepatic steatosis; Hepatocytes - drug effects; High fat diet; Hyperglycemia; Imidazoles - adverse effects; Imidazoles - pharmacology; Inflammation; Inhibitors; Insulin; Insulin - blood; Insulin resistance; insulin signaling; Insulin-like growth factor I; Intercellular Signaling Peptides and Proteins - metabolism; Intolerance; Kinases; Linagliptin - pharmacology; Lipoatrophy; Lipogenesis; Liver; Male; Metabolism; Methyltransferase; Mice, Inbred C57BL; N-Methyltransferase; Nicotinamide; Nicotinamide N-methyltransferase; Non-alcoholic Fatty Liver Disease - chemically induced; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Oral administration; Oxidative stress; Peptides; Perilipin-2 - metabolism; Proteins; proteomics; Pyrazines - adverse effects; Pyrazines - pharmacology; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, Insulin - antagonists & inhibitors; Steatosis; Steroid Hydroxylases - metabolism; Triglycerides - blood
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21217815

Abnormal hepatic insulin signaling is a cause or consequence of hepatic steatosis. DPP-4 inhibitors might be protective against fatty liver. We previously reported that the systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by the administration of OSI-906 (linsitinib), a dual IR/IGF1R inhibitor, induced glucose intolerance, hepatic steatosis, and lipoatrophy in mice. In the present study, we investigated the effects of a DPP-4 inhibitor, linagliptin, on hepatic steatosis in OSI-906-treated mice. Unlike high-fat diet-induced hepatic steatosis, OSI-906-induced hepatic steatosis is not characterized by elevations in inflammatory responses or oxidative stress levels. Linagliptin improved OSI-906-induced hepatic steatosis via an insulin-signaling-independent pathway, without altering glucose levels, free fatty acid levels, gluconeogenic gene expressions in the liver, or visceral fat atrophy. Hepatic quantitative proteomic and phosphoproteomic analyses revealed that perilipin-2 (PLIN2), major urinary protein 20 (MUP20), cytochrome P450 2b10 (CYP2B10), and nicotinamide N-methyltransferase (NNMT) are possibly involved in the process of the amelioration of hepatic steatosis by linagliptin. Thus, linagliptin improved hepatic steatosis induced by IR and IGF1R inhibition via a previously unknown mechanism that did not involve gluconeogenesis, lipogenesis, or inflammation, suggesting the non-canonical actions of DPP-4 inhibitors in the treatment of hepatic steatosis under insulin-resistant conditions.