title: Preventing phosphorylation of sterol regulatory element-binding protein 1a by MAP-kinases protects mice from fatty liver and visceral obesity.
abstract: 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.
authors.affiliation: Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at the Heinrich-Heine-University Duesseldorf, Leibniz Center for Diabetes Research, Duesseldorf, Germany.
authors.forename: Jorg
authors.initials: J
authors.lastname: Kotzka
authors.forename: Birgit
authors.initials: B
authors.lastname: Knebel
authors.forename: Jutta
authors.initials: J
authors.lastname: Haas
authors.forename: Lorena
authors.initials: L
authors.lastname: Kremer
authors.forename: Sylvia
authors.initials: S
authors.lastname: Jacob
authors.forename: Sonja
authors.initials: S
authors.lastname: Hartwig
authors.forename: Ulrike
authors.initials: U
authors.lastname: Nitzgen
authors.forename: Dirk
authors.initials: D
authors.lastname: Muller-Wieland
mesh_terms: D000818:Animals; D001665:Binding Sites; D004247:DNA / Q000737:chemistry; D005234:Fatty Liver / Q000201:enzymology / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D056128:Obesity, Abdominal / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D011485:Protein Binding; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D051780:Sterol Regulatory Element Binding Protein 1; D004247:DNA; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4