Preventing phosphorylation of sterol regulatory element-binding protein 1a by MAP-kinases protects mice from fatty liver and visceral obesity.
The transcription factor sterol regulatory element binding protein (SREBP)-1a plays a pivotal role in lipid metabolism. Using the SREBP-1a expressing human hepatoma cell line HepG2 we have shown previously that human SREBP-1a is phosphorylated at serine 117 by ERK-mitogen-activated protein kinases (...
Guardado en:
Autores principales: | , , , , , , , |
---|---|
Formato: | article |
Lenguaje: | EN |
Publicado: |
Public Library of Science (PLoS)
2012
|
Materias: | |
Acceso en línea: | https://doaj.org/article/b52abde8b11944ba986e7eb1ed77dd87 |
Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
id |
oai:doaj.org-article:b52abde8b11944ba986e7eb1ed77dd87 |
---|---|
record_format |
dspace |
spelling |
oai:doaj.org-article:b52abde8b11944ba986e7eb1ed77dd872021-11-18T07:26:37ZPreventing phosphorylation of sterol regulatory element-binding protein 1a by MAP-kinases protects mice from fatty liver and visceral obesity.1932-620310.1371/journal.pone.0032609https://doaj.org/article/b52abde8b11944ba986e7eb1ed77dd872012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22384276/?tool=EBIhttps://doaj.org/toc/1932-6203The transcription factor sterol regulatory element binding protein (SREBP)-1a plays a pivotal role in lipid metabolism. Using the SREBP-1a expressing human hepatoma cell line HepG2 we have shown previously that human SREBP-1a is phosphorylated at serine 117 by ERK-mitogen-activated protein kinases (MAPK). Using a combination of cell biology and protein chemistry approach we show that SREBP-1a is also target of other MAPK-families, i.e. c-JUN N-terminal protein kinases (JNK) or p38 stress activated MAP kinases. Serine 117 is also the major phosphorylation site in SREBP-1a for JNK. In contrast to that the major phosphorylation sites of p38 MAPK family are serine 63 and threonine 426. Functional analyses reveal that phosphorylation of SREBP-1a does not alter protein/DNA interaction. The identified phosphorylation sites are specific for both kinase families also in cellular context. To provide direct evidence that phosphorylation of SREBP-1a is a regulatory principle of biological and clinical relevance, we generated transgenic mice expressing mature transcriptionally active N-terminal domain of human SREBP-1a variant lacking all identified phosphorylaton sites designed as alb-SREBP-1aΔP and wild type SREBP-1a designed as alb-SREBP-1a liver specific under control of the albumin promoter and a liver specific enhancer. In contrast to alb-SREBP-1a mice the phosphorylation-deficient mice develop no enlarged fatty livers under normocaloric conditions. Phenotypical examination reveales a massive accumulation of adipose tissue in alb-SREBP-1a but not in the phosphorylation deficient alb-SREBP-1aΔP mice. Moreover, preventing phosphorylation of SREBP-1a protects mice also from dyslipidemia. In conclusion, phosphorylation of SREBP-1a by ERK, JNK and p38 MAPK-families resembles a biological principle and plays a significant role, in vivo.Jorg KotzkaBirgit KnebelJutta HaasLorena KremerSylvia JacobSonja HartwigUlrike NitzgenDirk Muller-WielandPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 2, p e32609 (2012) |
institution |
DOAJ |
collection |
DOAJ |
language |
EN |
topic |
Medicine R Science Q |
spellingShingle |
Medicine R Science Q Jorg Kotzka Birgit Knebel Jutta Haas Lorena Kremer Sylvia Jacob Sonja Hartwig Ulrike Nitzgen Dirk Muller-Wieland Preventing phosphorylation of sterol regulatory element-binding protein 1a by MAP-kinases protects mice from fatty liver and visceral obesity. |
description |
The transcription factor sterol regulatory element binding protein (SREBP)-1a plays a pivotal role in lipid metabolism. Using the SREBP-1a expressing human hepatoma cell line HepG2 we have shown previously that human SREBP-1a is phosphorylated at serine 117 by ERK-mitogen-activated protein kinases (MAPK). Using a combination of cell biology and protein chemistry approach we show that SREBP-1a is also target of other MAPK-families, i.e. c-JUN N-terminal protein kinases (JNK) or p38 stress activated MAP kinases. Serine 117 is also the major phosphorylation site in SREBP-1a for JNK. In contrast to that the major phosphorylation sites of p38 MAPK family are serine 63 and threonine 426. Functional analyses reveal that phosphorylation of SREBP-1a does not alter protein/DNA interaction. The identified phosphorylation sites are specific for both kinase families also in cellular context. To provide direct evidence that phosphorylation of SREBP-1a is a regulatory principle of biological and clinical relevance, we generated transgenic mice expressing mature transcriptionally active N-terminal domain of human SREBP-1a variant lacking all identified phosphorylaton sites designed as alb-SREBP-1aΔP and wild type SREBP-1a designed as alb-SREBP-1a liver specific under control of the albumin promoter and a liver specific enhancer. In contrast to alb-SREBP-1a mice the phosphorylation-deficient mice develop no enlarged fatty livers under normocaloric conditions. Phenotypical examination reveales a massive accumulation of adipose tissue in alb-SREBP-1a but not in the phosphorylation deficient alb-SREBP-1aΔP mice. Moreover, preventing phosphorylation of SREBP-1a protects mice also from dyslipidemia. In conclusion, phosphorylation of SREBP-1a by ERK, JNK and p38 MAPK-families resembles a biological principle and plays a significant role, in vivo. |
format |
article |
author |
Jorg Kotzka Birgit Knebel Jutta Haas Lorena Kremer Sylvia Jacob Sonja Hartwig Ulrike Nitzgen Dirk Muller-Wieland |
author_facet |
Jorg Kotzka Birgit Knebel Jutta Haas Lorena Kremer Sylvia Jacob Sonja Hartwig Ulrike Nitzgen Dirk Muller-Wieland |
author_sort |
Jorg Kotzka |
title |
Preventing phosphorylation of sterol regulatory element-binding protein 1a by MAP-kinases protects mice from fatty liver and visceral obesity. |
title_short |
Preventing phosphorylation of sterol regulatory element-binding protein 1a by MAP-kinases protects mice from fatty liver and visceral obesity. |
title_full |
Preventing phosphorylation of sterol regulatory element-binding protein 1a by MAP-kinases protects mice from fatty liver and visceral obesity. |
title_fullStr |
Preventing phosphorylation of sterol regulatory element-binding protein 1a by MAP-kinases protects mice from fatty liver and visceral obesity. |
title_full_unstemmed |
Preventing phosphorylation of sterol regulatory element-binding protein 1a by MAP-kinases protects mice from fatty liver and visceral obesity. |
title_sort |
preventing phosphorylation of sterol regulatory element-binding protein 1a by map-kinases protects mice from fatty liver and visceral obesity. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2012 |
url |
https://doaj.org/article/b52abde8b11944ba986e7eb1ed77dd87 |
work_keys_str_mv |
AT jorgkotzka preventingphosphorylationofsterolregulatoryelementbindingprotein1abymapkinasesprotectsmicefromfattyliverandvisceralobesity AT birgitknebel preventingphosphorylationofsterolregulatoryelementbindingprotein1abymapkinasesprotectsmicefromfattyliverandvisceralobesity AT juttahaas preventingphosphorylationofsterolregulatoryelementbindingprotein1abymapkinasesprotectsmicefromfattyliverandvisceralobesity AT lorenakremer preventingphosphorylationofsterolregulatoryelementbindingprotein1abymapkinasesprotectsmicefromfattyliverandvisceralobesity AT sylviajacob preventingphosphorylationofsterolregulatoryelementbindingprotein1abymapkinasesprotectsmicefromfattyliverandvisceralobesity AT sonjahartwig preventingphosphorylationofsterolregulatoryelementbindingprotein1abymapkinasesprotectsmicefromfattyliverandvisceralobesity AT ulrikenitzgen preventingphosphorylationofsterolregulatoryelementbindingprotein1abymapkinasesprotectsmicefromfattyliverandvisceralobesity AT dirkmullerwieland preventingphosphorylationofsterolregulatoryelementbindingprotein1abymapkinasesprotectsmicefromfattyliverandvisceralobesity |
_version_ |
1718423433208922112 |