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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

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...

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Autores principales: Knebel, Birgit, Hartwig, Sonja, Jacob, Sylvia, Kettel, Ulrike, Schiller, Martina, Passlack, Waltraud, Koellmer, Cornelia, Lehr, Stefan, Müller-Wieland, Dirk, Kotzka, Jorg
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979561/
https://www.ncbi.nlm.nih.gov/pubmed/29587401
http://dx.doi.org/10.3390/ijms19040980
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author Knebel, Birgit
Hartwig, Sonja
Jacob, Sylvia
Kettel, Ulrike
Schiller, Martina
Passlack, Waltraud
Koellmer, Cornelia
Lehr, Stefan
Müller-Wieland, Dirk
Kotzka, Jorg
author_facet Knebel, Birgit
Hartwig, Sonja
Jacob, Sylvia
Kettel, Ulrike
Schiller, Martina
Passlack, Waltraud
Koellmer, Cornelia
Lehr, Stefan
Müller-Wieland, Dirk
Kotzka, Jorg
author_sort Knebel, Birgit
collection PubMed
description 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.
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spelling pubmed-59795612018-06-10 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 Knebel, Birgit Hartwig, Sonja Jacob, Sylvia Kettel, Ulrike Schiller, Martina Passlack, Waltraud Koellmer, Cornelia Lehr, Stefan Müller-Wieland, Dirk Kotzka, Jorg Int J Mol Sci Article 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. MDPI 2018-03-25 /pmc/articles/PMC5979561/ /pubmed/29587401 http://dx.doi.org/10.3390/ijms19040980 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Knebel, Birgit
Hartwig, Sonja
Jacob, Sylvia
Kettel, Ulrike
Schiller, Martina
Passlack, Waltraud
Koellmer, Cornelia
Lehr, Stefan
Müller-Wieland, Dirk
Kotzka, Jorg
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979561/
https://www.ncbi.nlm.nih.gov/pubmed/29587401
http://dx.doi.org/10.3390/ijms19040980
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