Abstract
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.
Highlights
The prevalence of patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), which are associated with diabetes and metabolic syndrome, have increased considerably [1,2]
Wild-type C57BL/6J mice were orally injected with OSI-906 at a dosage of 45 mg/day, thereby blunting Insulin receptor (IR)- and IGF-1 receptor (IGF1R)-mediated signaling in the liver and white adipose tissue [10,12]
We reported that the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin ameliorated hepatic steatosis elicited by the dual IR/IGF1R inhibitor OSI-906
Summary
The prevalence of patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), which are associated with diabetes and metabolic syndrome, have increased considerably [1,2]. We previously reported that the oral administration of OSI-906 for 7 days induced glucose intolerance, liver steatosis, and lipoatrophy in mice [10,11]. In this model, insulin signaling in the liver was completely abolished [12]. The inhibition of DPP-4 extends the half-life of endogenous active forms of GIP and GLP-1, and lowers hyperglycemia in patients with type 2 diabetes. In addition to their glucose-lowering effects, DPP-4 inhibitors reportedly have multiple pleiotropic effects that are independent of its pancreatic effects. 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
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