The liver plays a crucial role in maintaining homeostasis for lipid and glucose. Hepatic lipid synthesis is regulated by nutritional signals in response to fasting and refeeding. It is known that overnutrition regulates MAPK-dependent pathways that control lipid metabolism in the liver by activating MAPK phosphatase-2 (MKP-2). Uncertainty still exists regarding the regulatory mechanisms and effects of MKP-2 on hepatic response to fasting. We investigated the effect of fasting on the expression of MKP-2 and the impact on hepatic inflammatory response to feeding a high-fat diet (HFD). In this study, we show that fasting stress led to an upregulation of hepatic MKP-2 expression and a corresponding decrease in phosphorylation of p38 MAPK in mouse livers. We discovered that hepatic steatosis brought on by fasting is not effective in MKP-2-deficient livers due in part to a decrease in lipolysis and GLUT2 expression. In response to refeeding a chow or HFD, MKP-2 exhibited differential regulation of hepatic inflammatory cytokines including IL-1β. It has been demonstrated that the mitochondrial carrier uncoupling protein 2 (UCP2) plays a significant role in immune function. We discovered that MKP-2 negatively controls the expression of the UCP2 protein in the liver, modulating the expression of inflammatory cytokines. These results lend credence to the idea that upregulation of MKP-2 is a physiologically relevant response and may help the liver better utilize hepatic lipids while fasting. Collectively, these findings show that MKP-2 modulates lipolysis and hepatic inflammatory response in response to alterations in nutritional status, such as excess nutrients and fasting.

Cytokines, Fasting, Liver inflammation, Mitogen-activated protein kinase, Protein tyrosine phosphatase, Uncoupling protein-2