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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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 |
format | Online Article Text |
id | pubmed-8619756 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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