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Open AccessArticle

Inactivation of SREBP-1a Phosphorylation Prevents Fatty Liver Disease in Mice: Identification of Related Signaling Pathways by Gene Expression Profiles in Liver and Proteomes of Peroxisomes

1
Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at the Heinrich-Heine-University Duesseldorf, Leibniz Center for Diabetes Research, Aufm Hennekamp 65, 40225 Duesseldorf, Germany
2
German Center of Diabetes Research Partner, 40225 Duesseldorf, Germany
3
Clinical Research Centre, Department of Internal Medicine I, University Hospital Aachen, 52074 Aachen, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(4), 980; https://doi.org/10.3390/ijms19040980
Received: 23 February 2018 / Revised: 19 March 2018 / Accepted: 22 March 2018 / Published: 25 March 2018
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
The key lipid metabolism transcription factor sterol regulatory element-binding protein (SREBP)-1a integrates gene regulatory effects of hormones, cytokines, nutrition and metabolites as lipids, glucose, or cholesterol via phosphorylation by different mitogen activated protein kinase (MAPK) cascades. We have previously reported the impact of SREBP-1a phosphorylation on the phenotype in transgenic mouse models with liver-specific overexpression of the N-terminal transcriptional active domain of SREBP-1a (alb-SREBP-1a) or a MAPK phosphorylation site-deficient variant (alb-SREBP-1a∆P; (S63A, S117A, T426V)), respectively. In this report, we investigated the molecular basis of the systemic observations by holistic analyses of gene expression in liver and of proteome patterns in lipid-degrading organelles involved in the pathogenesis of metabolic syndrome, i.e., peroxisomes, using 2D-DIGE and mass spectrometry. The differences in hepatic gene expression and peroxisomal protein patterns were surprisingly small between the control and alb-SREBP-1a mice, although the latter develop a severe phenotype with visceral obesity and fatty liver. In contrast, phosphorylation site-deficient alb-SREBP-1a∆P mice, which are protected from fatty liver disease, showed marked differences in hepatic gene expression and peroxisomal proteome patterns. Further knowledge-based analyses revealed that disruption of SREBP-1a phosphorylation resulted in massive alteration of cellular processes, including signs for loss of targeting lipid pathways. View Full-Text
Keywords: phosphorylation of SREBP-1a; hepatic gene expression; peroxisome proteome; phosphorylation in lipid metabolism; liver peroxisomes; metabolic syndrome; fatty liver; olfactory receptors phosphorylation of SREBP-1a; hepatic gene expression; peroxisome proteome; phosphorylation in lipid metabolism; liver peroxisomes; metabolic syndrome; fatty liver; olfactory receptors
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MDPI and ACS Style

Knebel, B.; Hartwig, S.; Jacob, S.; Kettel, U.; Schiller, M.; Passlack, W.; Koellmer, C.; Lehr, S.; Müller-Wieland, D.; Kotzka, J. Inactivation of SREBP-1a Phosphorylation Prevents Fatty Liver Disease in Mice: Identification of Related Signaling Pathways by Gene Expression Profiles in Liver and Proteomes of Peroxisomes. Int. J. Mol. Sci. 2018, 19, 980. https://doi.org/10.3390/ijms19040980

AMA Style

Knebel B, Hartwig S, Jacob S, Kettel U, Schiller M, Passlack W, Koellmer C, Lehr S, Müller-Wieland D, Kotzka J. Inactivation of SREBP-1a Phosphorylation Prevents Fatty Liver Disease in Mice: Identification of Related Signaling Pathways by Gene Expression Profiles in Liver and Proteomes of Peroxisomes. International Journal of Molecular Sciences. 2018; 19(4):980. https://doi.org/10.3390/ijms19040980

Chicago/Turabian Style

Knebel, Birgit; Hartwig, Sonja; Jacob, Sylvia; Kettel, Ulrike; Schiller, Martina; Passlack, Waltraud; Koellmer, Cornelia; Lehr, Stefan; Müller-Wieland, Dirk; Kotzka, Jorg. 2018. "Inactivation of SREBP-1a Phosphorylation Prevents Fatty Liver Disease in Mice: Identification of Related Signaling Pathways by Gene Expression Profiles in Liver and Proteomes of Peroxisomes" Int. J. Mol. Sci. 19, no. 4: 980. https://doi.org/10.3390/ijms19040980

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