1. INTRODUCTION
The prevalences of patients with non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), which are associated with diabetes and metabolic syndrome, have increased considerably (Ahmadieh & Azar, 2014; Sanyal, 2002). Hepatic insulin action through growth hormone receptors-mediated signaling is involved in the development of fatty liver (Michael et al., 2000). Fat accumulation in the liver has also been found to cause hepatic insulin resistance (Samuel et al., 2004).
Insulin receptor (IR) and IGF-1 receptor (IGF1R) play roles in systemic metabolic actions, cell proliferation and migration, as well as cancer growth and metastasis (Belfiore, Frasca, Pandini, Sciacca & Vigneri, 2009; Djiogue et al., 2013). Previously, a number of anti-IGF-1 receptor drugs, including monoclonal antibodies and tyrosine kinase inhibitors, have been developed as anti-tumor drugs (Garcia-Echeverria, 2006; Rodon, DeSantos, Ferry & Kurzrock, 2008). OSI-906 (linsitinib) is an orally bioavailable dual IR/IGF1R tyrosine kinase inhibitor (Mulvihill et al., 2009). OSI-906 specifically inhibits the autophosphorylation of IR/IGF1R and their downstream pathways, resulting in the induction of insulin resistance. We previously reported that the oral administration of OSI-906 for 7 days induced glucose intolerance, liver steatosis, and lipoatrophy in mice (Shirakawa et al., 2014; Tajima et al., 2017). In this model, insulin signaling in the liver was completely abolished (Shirakawa et al., 2020).
Linagliptin, a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, is mainly excreted in feces, though most DPP-4 inhibitors are cleared by the kidneys (Blech, Ludwig-Schwellinger, Grafe-Mody, Withopf & Wagner, 2010). The functions of incretins are thought to potentiate glucose-dependent insulin secretion from pancreatic β-cells, inhibiting glucagon secretion; this in turn reduces hepatic gluconeogenesis. In addition to their glucose-lowering effects, DPP-4 inhibitors reportedly have multiple pleiotropic effects that are independent of its pancreatic effects. Reportedly, DPP-4 inhibitors might ameliorate NAFLD in patients with type 2 diabetes (Carbone, Angus & Yeomans, 2016; Samson & Bajaj, 2013). DPP-4 inhibitors also reduced hepatic fat accumulation in experimental models of NAFLD (Kern et al., 2012; Klein et al., 2014). However, the mechanisms responsible for the protective effects of DPP-4 inhibition on fatty liver are obscure.
In this study, we administered the DPP-4 inhibitor linagliptin to OSI-906-injected mice to investigate whether linagliptin ameliorates fatty liver under the conditions of IR and IGF1R inhibition.