Lysophosphatidic acid counteracts glucagon-induced hepatocyte glucose production via STAT3

Abstract Hepatic glucose production (HGP) is required to maintain normoglycemia during fasting. Glucagon is the primary hormone responsible for increasing HGP; however, there are many additional hormone and metabolic factors that influence glucagon sensitivity. In this study we report that the bioac...

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Autores principales:	Evan P. Taddeo, Stefan R. Hargett, Sujoy Lahiri, Marin E. Nelson, Jason A. Liao, Chien Li, Jill K. Slack-Davis, Jose L. Tomsig, Kevin R. Lynch, Zhen Yan, Thurl E. Harris, Kyle L. Hoehn
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e280b7810e98472f94e89b5b849f2537
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spelling	oai:doaj.org-article:e280b7810e98472f94e89b5b849f25372021-12-02T16:07:58ZLysophosphatidic acid counteracts glucagon-induced hepatocyte glucose production via STAT310.1038/s41598-017-00210-y2045-2322https://doaj.org/article/e280b7810e98472f94e89b5b849f25372017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00210-yhttps://doaj.org/toc/2045-2322Abstract Hepatic glucose production (HGP) is required to maintain normoglycemia during fasting. Glucagon is the primary hormone responsible for increasing HGP; however, there are many additional hormone and metabolic factors that influence glucagon sensitivity. In this study we report that the bioactive lipid lysophosphatidic acid (LPA) regulates hepatocyte glucose production by antagonizing glucagon-induced expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK). Treatment of primary hepatocytes with exogenous LPA blunted glucagon-induced PEPCK expression and glucose production. Similarly, knockout mice lacking the LPA-degrading enzyme phospholipid phosphate phosphatase type 1 (PLPP1) had a 2-fold increase in endogenous LPA levels, reduced PEPCK levels during fasting, and decreased hepatic gluconeogenesis in response to a pyruvate challenge. Mechanistically, LPA antagonized glucagon-mediated inhibition of STAT3, a transcriptional repressor of PEPCK. Importantly, LPA did not blunt glucagon-stimulated glucose production or PEPCK expression in hepatocytes lacking STAT3. These data identify a novel role for PLPP1 activity and hepatocyte LPA levels in glucagon sensitivity via a mechanism involving STAT3.Evan P. TaddeoStefan R. HargettSujoy LahiriMarin E. NelsonJason A. LiaoChien LiJill K. Slack-DavisJose L. TomsigKevin R. LynchZhen YanThurl E. HarrisKyle L. HoehnNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Evan P. Taddeo Stefan R. Hargett Sujoy Lahiri Marin E. Nelson Jason A. Liao Chien Li Jill K. Slack-Davis Jose L. Tomsig Kevin R. Lynch Zhen Yan Thurl E. Harris Kyle L. Hoehn Lysophosphatidic acid counteracts glucagon-induced hepatocyte glucose production via STAT3
description	Abstract Hepatic glucose production (HGP) is required to maintain normoglycemia during fasting. Glucagon is the primary hormone responsible for increasing HGP; however, there are many additional hormone and metabolic factors that influence glucagon sensitivity. In this study we report that the bioactive lipid lysophosphatidic acid (LPA) regulates hepatocyte glucose production by antagonizing glucagon-induced expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK). Treatment of primary hepatocytes with exogenous LPA blunted glucagon-induced PEPCK expression and glucose production. Similarly, knockout mice lacking the LPA-degrading enzyme phospholipid phosphate phosphatase type 1 (PLPP1) had a 2-fold increase in endogenous LPA levels, reduced PEPCK levels during fasting, and decreased hepatic gluconeogenesis in response to a pyruvate challenge. Mechanistically, LPA antagonized glucagon-mediated inhibition of STAT3, a transcriptional repressor of PEPCK. Importantly, LPA did not blunt glucagon-stimulated glucose production or PEPCK expression in hepatocytes lacking STAT3. These data identify a novel role for PLPP1 activity and hepatocyte LPA levels in glucagon sensitivity via a mechanism involving STAT3.
format	article
author	Evan P. Taddeo Stefan R. Hargett Sujoy Lahiri Marin E. Nelson Jason A. Liao Chien Li Jill K. Slack-Davis Jose L. Tomsig Kevin R. Lynch Zhen Yan Thurl E. Harris Kyle L. Hoehn
author_facet	Evan P. Taddeo Stefan R. Hargett Sujoy Lahiri Marin E. Nelson Jason A. Liao Chien Li Jill K. Slack-Davis Jose L. Tomsig Kevin R. Lynch Zhen Yan Thurl E. Harris Kyle L. Hoehn
author_sort	Evan P. Taddeo
title	Lysophosphatidic acid counteracts glucagon-induced hepatocyte glucose production via STAT3
title_short	Lysophosphatidic acid counteracts glucagon-induced hepatocyte glucose production via STAT3
title_full	Lysophosphatidic acid counteracts glucagon-induced hepatocyte glucose production via STAT3
title_fullStr	Lysophosphatidic acid counteracts glucagon-induced hepatocyte glucose production via STAT3
title_full_unstemmed	Lysophosphatidic acid counteracts glucagon-induced hepatocyte glucose production via STAT3
title_sort	lysophosphatidic acid counteracts glucagon-induced hepatocyte glucose production via stat3
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e280b7810e98472f94e89b5b849f2537
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Lysophosphatidic acid counteracts glucagon-induced hepatocyte glucose production via STAT3

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