3.4. Linagliptin exerts direct and indirect effects on
hepatocytes during the improvement of hepatic steatosis
To elucidate whether the effect of linagliptin on hepatic steatosis was
mediated through the direct action of linagliptin, GLP-1 receptor
signaling in hepatocytes, or an indirect pathway through components such
as humoral factors, we treated hepatocyte AML-12 cells with the DPP-4
inhibitor linagliptin or the GLP-1 receptor agonist liraglutide in the
presence of OSI-906 (Figure 7). In AML-12 hepatocyte cells, linagliptin
did not reverse the effects of OSI-906 on gluconeogenic gene
expressions, consistent with the in vivo results. In contrast,
the decrease in Tnf expression in OSI-906-treated cells was not
reversed by incubation with linagliptin or liraglutide, unlike thein vivo results, implying an indirect effect of linagliptin and
DPP-4 inhibition on hepatocytes. In contrast, liraglutide canceled the
OSI-906-induced increases in gluconeogenic gene expressions. The
expression of Plin2 was induced by OSI-906 and was diminished by
the treatment with linagliptin, but not with liraglutide. These results
indicate that linagliptin influences hepatocytes through multiple
mechanisms that are independent of GLP-1 receptor signaling.