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Fasting-Induced Upregulation of MKP-1 Modulates the Hepatic Response to Feeding.

Authors :
Sellers J
Brooks A
Fernando S
Westenberger G
Junkins S
Smith S
Min K
Lawan A
Source :
Nutrients [Nutrients] 2021 Nov 04; Vol. 13 (11). Date of Electronic Publication: 2021 Nov 04.
Publication Year :
2021

Abstract

The liver plays a key role in whole-body, glucose and lipid homeostasis. Nutritional signals in response to fasting and refeeding regulate hepatic lipid synthesis. It is established that activation of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) in response to overnutrition regulates MAPK-dependent pathways that control lipid metabolism in the liver. However, the regulatory mechanisms and the impact of the actions of MKP-1 in hepatic response to fasting remains unclear. We investigated the effect of fasting on the expression of MKP-1 and the impact on hepatic response to feeding. In this study, we demonstrate that fasting stress induced upregulation of hepatic MKP-1 protein levels with a corresponding downregulation of p38 MAPK and JNK phosphorylation in mouse livers. We found that MKP-1-deficient livers are resistant to fasting-induced hepatic steatosis. Hepatic MKP-1 deficiency impaired fasting-induced changes in the levels of key transcription factors involved in the regulation of fatty acid and cholesterol metabolism including Srebf2 and Srebf1c . Mechanistically, MKP-1 negatively regulates Srebf2 expression by attenuating p38 MAPK pathway, suggesting its contribution to the metabolic effects of MKP-1 deficiency in the fasting liver. These findings support the hypothesis that upregulation of MKP-1 is a physiological relevant response and might be beneficial in hepatic lipid utilization during fasting in the liver. Collectively, these data unravel some of the complexity and tissue specific interaction of MKP-1 action in response to changes in nutritional cues, including fasting and excess nutrients.

Details

Language :
English
ISSN :
2072-6643
Volume :
13
Issue :
11
Database :
MEDLINE
Journal :
Nutrients
Publication Type :
Academic Journal
Accession number :
34836195
Full Text :
https://doi.org/10.3390/nu13113941