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:	Jacob Sellers, Abigail Brooks, Savanie Fernando, Gabrielle Westenberger, Sadie Junkins, Shauri Smith, Kisuk Min, Ahmed Lawan
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	fasting mitogen-activated protein kinase protein tyrosine phosphatase obesity cholesterol fatty acid biosynthesis Nutrition. Foods and food supply TX341-641
Acceso en línea:	https://doaj.org/article/9eaa67d0cc9a467ca74702e019bd9e49
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spelling	oai:doaj.org-article:9eaa67d0cc9a467ca74702e019bd9e492021-11-25T18:35:28ZFasting-Induced Upregulation of MKP-1 Modulates the Hepatic Response to Feeding10.3390/nu131139412072-6643https://doaj.org/article/9eaa67d0cc9a467ca74702e019bd9e492021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6643/13/11/3941https://doaj.org/toc/2072-6643The 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 <i>Srebf2</i> and <i>Srebf1c</i>. Mechanistically, MKP-1 negatively regulates <i>Srebf2</i> 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 nutrientsJacob SellersAbigail BrooksSavanie FernandoGabrielle WestenbergerSadie JunkinsShauri SmithKisuk MinAhmed LawanMDPI AGarticlefastingmitogen-activated protein kinaseprotein tyrosine phosphataseobesitycholesterolfatty acid biosynthesisNutrition. Foods and food supplyTX341-641ENNutrients, Vol 13, Iss 3941, p 3941 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	fasting mitogen-activated protein kinase protein tyrosine phosphatase obesity cholesterol fatty acid biosynthesis Nutrition. Foods and food supply TX341-641
spellingShingle	fasting mitogen-activated protein kinase protein tyrosine phosphatase obesity cholesterol fatty acid biosynthesis Nutrition. Foods and food supply TX341-641 Jacob Sellers Abigail Brooks Savanie Fernando Gabrielle Westenberger Sadie Junkins Shauri Smith Kisuk Min Ahmed Lawan Fasting-Induced Upregulation of MKP-1 Modulates the Hepatic Response to Feeding
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 <i>Srebf2</i> and <i>Srebf1c</i>. Mechanistically, MKP-1 negatively regulates <i>Srebf2</i> 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	article
author	Jacob Sellers Abigail Brooks Savanie Fernando Gabrielle Westenberger Sadie Junkins Shauri Smith Kisuk Min Ahmed Lawan
author_facet	Jacob Sellers Abigail Brooks Savanie Fernando Gabrielle Westenberger Sadie Junkins Shauri Smith Kisuk Min Ahmed Lawan
author_sort	Jacob Sellers
title	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_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_sort	fasting-induced upregulation of mkp-1 modulates the hepatic response to feeding
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/9eaa67d0cc9a467ca74702e019bd9e49
work_keys_str_mv	AT jacobsellers fastinginducedupregulationofmkp1modulatesthehepaticresponsetofeeding AT abigailbrooks fastinginducedupregulationofmkp1modulatesthehepaticresponsetofeeding AT savaniefernando fastinginducedupregulationofmkp1modulatesthehepaticresponsetofeeding AT gabriellewestenberger fastinginducedupregulationofmkp1modulatesthehepaticresponsetofeeding AT sadiejunkins fastinginducedupregulationofmkp1modulatesthehepaticresponsetofeeding AT shaurismith fastinginducedupregulationofmkp1modulatesthehepaticresponsetofeeding AT kisukmin fastinginducedupregulationofmkp1modulatesthehepaticresponsetofeeding AT ahmedlawan fastinginducedupregulationofmkp1modulatesthehepaticresponsetofeeding
_version_	1718410968841584640

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

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