Linagliptin ameliorates hepatic steatosis via non-canonical mechanisms
in mice treated with a dual inhibitor of insulin receptor and IGF-1
receptor
Abstract
ABSTRACT Background and Purpose: 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. Experimental
Approach: We treated C57BL/6J male mice either with vehicle,
linagliptin, OSI-906 or OSI-906 + linagliptin for 7 days. We also
conducted proteomic and phosphoproteomic analyses of the liver from
those mice. Key Results: 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), nicotinamide N-methyltransferase (NNMT), and
sirtuin families are possibly involved in the process of the
amelioration of hepatic steatosis by linagliptin. Conclusion and
Implications: 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.