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

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 regulate...

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Autores principales: Sellers, Jacob, Brooks, Abigail, Fernando, Savanie, Westenberger, Gabrielle, Junkins, Sadie, Smith, Shauri, Min, Kisuk, Lawan, Ahmed
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619756/
https://www.ncbi.nlm.nih.gov/pubmed/34836195
http://dx.doi.org/10.3390/nu13113941
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author Sellers, Jacob
Brooks, Abigail
Fernando, Savanie
Westenberger, Gabrielle
Junkins, Sadie
Smith, Shauri
Min, Kisuk
Lawan, Ahmed
author_facet Sellers, Jacob
Brooks, Abigail
Fernando, Savanie
Westenberger, Gabrielle
Junkins, Sadie
Smith, Shauri
Min, Kisuk
Lawan, Ahmed
author_sort Sellers, Jacob
collection PubMed
description 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
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spelling pubmed-86197562021-11-27 Fasting-Induced Upregulation of MKP-1 Modulates the Hepatic Response to Feeding Sellers, Jacob Brooks, Abigail Fernando, Savanie Westenberger, Gabrielle Junkins, Sadie Smith, Shauri Min, Kisuk Lawan, Ahmed Nutrients Article 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 MDPI 2021-11-04 /pmc/articles/PMC8619756/ /pubmed/34836195 http://dx.doi.org/10.3390/nu13113941 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sellers, Jacob
Brooks, Abigail
Fernando, Savanie
Westenberger, Gabrielle
Junkins, Sadie
Smith, Shauri
Min, Kisuk
Lawan, Ahmed
Fasting-Induced Upregulation of MKP-1 Modulates the Hepatic Response to Feeding
title Fasting-Induced Upregulation of MKP-1 Modulates the Hepatic Response to Feeding
title_full Fasting-Induced Upregulation of MKP-1 Modulates the Hepatic Response to Feeding
title_fullStr Fasting-Induced Upregulation of MKP-1 Modulates the Hepatic Response to Feeding
title_full_unstemmed Fasting-Induced Upregulation of MKP-1 Modulates the Hepatic Response to Feeding
title_short Fasting-Induced Upregulation of MKP-1 Modulates the Hepatic Response to Feeding
title_sort fasting-induced upregulation of mkp-1 modulates the hepatic response to feeding
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619756/
https://www.ncbi.nlm.nih.gov/pubmed/34836195
http://dx.doi.org/10.3390/nu13113941
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