A functional role of Macrophage Migration Inhibitory Factor (MIF) for liver steatosis in mice by activation of AMP kinase

Background: The cytokine macrophage migration inhibitory factor (MIF) is known to be involved in various inflammatory diseases. We have recently discovered an unexpected anti-fibrotic function of MIF in experimental mouse models which is mediated by activation of the stress kinase AMPK (Heinrichs et al. PNAS 2011). AMPK is also known to be involved in lipogenesis. We therefore assessed the specific role of MIF in hepatic steatosis in vivo and in vitro.

Methods: Male MIF knockout (Mif ^-/-) and wild-type mice were fed a high fat (60% fat/kcal, HFD) or a methionine and choline-deficient diet (MCD). Weight gain was assessed weekly. After 16 weeks of the HFD, a glucose tolerance test was performed before sacrificing the mice. Liver steatosis was analyzed by triglyceride content and intrahepatic mRNA expression of lipogenic genes (Lxra, Srebp1, Acc, Fas). In vitro, the effects of the MIF/CD74/AMPK signaling pathway on the fatty degeneration of hepatoma cells were analyzed.

Results: Mif ^-/- and wild-type mice showed no significant differences in weight gain on the HFD, but glucose sensitivity was reduced in Mif ^-/-. Notably, Mif ^-/- mice showed a significantly increased degree of liver steatosis in both steatosis models, as assessed by liver triglycerides and mRNA expression of genes involved in triglyceride synthesis, compared to wild-type mice. In vitro, recombinant MIF directly inhibited the fatty degeneration of hepatoma cells. This direct anti-steatogenic effect of MIF could be blocked by co-stimulation with compound C, an AMPK inhibitor, or by blocking the MIF receptor CD74.

Conclusion: Our results indicate a functional role of the cytokine MIF in the development of fatty liver disease which is mediated through CD74 and an increased AMPK activation in hepatocytes. These data imply MIF and its receptor CD74 as new targets for the treatment of liver steatosis.