title: Phosphorylation of sterol regulatory element-binding protein (SREBP)-1c by p38 kinases, ERK and JNK influences lipid metabolism and the secretome of human liver cell line HepG2.
abstract: The transcription factor sterol regulatory element binding protein (SREBP)-1c plays a pivotal role in lipid metabolism. In this report we identified the main phosphorylation sites of MAPK-families, i.e. p38 stress-activated MAPK (p38), ERK-MAPK (ERK) or c-JUN N-terminal protein kinases (JNK) in SREBP-1c. The major phosphorylation sites of p38, i.e. serine 39 and threonine 402, are identical to those we recently identified in the splice-variant SREBP-1a. In contrast, ERK and JNK phosphorylate SREBP-1c at two major sites, i.e. threonine 81 and serine 93, instead of one site in SREBP-1a. Functional analyses of the biological outcome in the human liver cell line HepG2 reveals SREBP-1c phosphorylation dependent alteration in lipid metabolism and secretion pattern of lipid transporting proteins, e.g. ApoE or ApoA1. These results suggest that phosphorylation of SREBP-1c by different MAPKs interferes with lipid metabolism and the secretory activity of liver cells.
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: Birgit
authors.initials: B
authors.lastname: Knebel
authors.forename: Stefan
authors.initials: S
authors.lastname: Lehr
authors.forename: Sonja
authors.initials: S
authors.lastname: Hartwig
authors.forename: Jutta
authors.initials: J
authors.lastname: Haas
authors.forename: Gernot
authors.initials: G
authors.lastname: Kaber
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Dicken
authors.forename: Franciscus
authors.initials: F
authors.lastname: Susanto
authors.forename: Lothar
authors.initials: L
authors.lastname: Bohne
authors.forename: Sylvia
authors.initials: S
authors.lastname: Jacob
authors.forename: Ulrike
authors.initials: U
authors.lastname: Nitzgen
authors.forename: Waltraud
authors.initials: W
authors.lastname: Passlack
authors.forename: Dirk
authors.initials: D
authors.lastname: Muller-Wieland
authors.forename: Jorg
authors.initials: J
authors.lastname: Kotzka
mesh_terms: D001665:Binding Sites; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D050356:Lipid Metabolism; D010766:Phosphorylation; D051780:Sterol Regulatory Element Binding Protein 1 / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D051780:Sterol Regulatory Element Binding Protein 1; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Dyslipidemia; NAFLD; fatty acids; hepatokine; secretome