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Hepatic phosphorylation of transcription factor SREBP-1a interferes with gene regulation and peroxisomal function

ABSTRACT: 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 stimuli specific phosphorylation by different MAPK cascades. We have formerly reported the systemic impact of phosphorylation in transgenic mouse models with liver-specific overexpression of the N-terminal transcriptional active domain of SREBP-1a (alb-SREBP-1a) or a MAPK kinase phosphorylation sites deficient variant (alb-SREBP-1a∆P; (S63A, S117A, T426V)), respectively. Here we investigated the molecular basis of the systemic observation in holistic hepatic gene expression analyses and lipid degrading organelles involved in the pathogenesis of metabolic syndrome, i.e. peroxisomes, by 2D-DIGE and mass spectrometry analyses. Although alb-SREBP-1a mice develop a severe phenotype with visceral adipositas and hepatic lipid accumulation featuring a fatty liver, the hepatic differential gene expression and alterations in peroxisomal protein patterns compared to control mice were surprisingly relative low. In contrast, phosphorylation site deficient alb-SREBP-1a∆P mice, protected from hepatic lipid accumulation phenotype, showed gross alteration in hepatic gene expression and peroxisomal proteome. Further knowledge based analyzes revealed that overexpression of SREBP-1a favored mainly acceleration in lipid metabolism and indicated a regular insulin signaling, whereas disruption of SREBP-1a phosphorylation resulted in massive alteration of cellular processes including signs for loss of lipid metabolic targets. These results could be the link to a disturbed lipid metabolism that overall resembles a state of insulin resistance.

OTHER RELATED OMICS DATASETS IN: PRJNA433992

ORGANISM(S): Mus musculus

PROVIDER: GSE110569 | GEO | 2018/03/30

REPOSITORIES: GEO

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Project description:Background and aim: The Insulin-like growth factor (IGF) axis is increasingly suggested to be involved in fatty liver disease and progression. We identified IGFBP2 as transcriptional regulatory effect network in liver steatosis and conducted a translational approach of its role in liver pathology from mouse to human, and whether it is influenced by conventional clinical intervention that mitigate hepatic steatosis. Methods: Primary hepatocytes from either C57Bl6 controls, alb-SREBP-1c mice with moderate transgene induced hepatic lipid accumulation or aP2-SREBP-1c mice with massive ectopic hepatic lipid accumulation, were analyzed to identify regulatory networks based on differentially regulated hepatic gene expression. In a translational approach, serum of morbidly obese patients with and without diabetes and biopsy-proven NAFLD were used for ELISA-based validation of mouse data. Moreover, sera of patients undergoing intervention were analyzed and correlated to liver fat content. Results: Comparative knowledge-based transcriptome analysis identified IGFBP2 as top score regulatory effect network between moderate and aggravated fatty liver in mouse models. The reduced expression of IGFBP2 in aP2-SREPB-1c progressed fatty liver associated with Igfbp2 promoter hypermethylation. Reduced secretion of IGFBP2 from aP2-SREBP-1c hepatocytes was reflected in the circulation of the animals. In this phenotype, reductions of IGFBP2 were accompanied by reduced fatty acid oxidation and increased methyltransferase and SIRT activity. Physiologically, IGFBP2 has no direct impact on lipid metabolism but might modulate IGF1 action on de novo lipogenesis. In humans, IGFBP2 levels declined from non-obese men to morbidly obese men with NAFLD and NASH. In intervention study reductions in liver fat correlated with restoration of IGFBP2 serum levels to values found in healthy individuals in morbidly obese patients following bariatric surgery. Conclusion: In hepatic metabolism changes of IGFBP2 abundance is connected to lipid metabolism whereas changes in IGFBP2 secretion were directly reflected in the circulation. IGFBP2 serum concentration correlates with the degree of fatty liver, which seems to be related to plasticity of the adipose tissue. These data provide IGFBP2 as a potential non-invasive biomarker for fatty liver disease directly reflecting the degree of impaired liver function with the potential to indicate progressed fatty liver disease.

Project description:The sterol regulatory element binding proteins (SREBPs) are transcription factors that govern cholesterol and fatty acid metabolism. Owing to their central role in controlling hepatic lipid and lipoprotein metabolism their activity is tightly coordinated, and accordingly dysregulation of the SREBP pathway is associated with development of dyslipidemia and non-alcoholic fatty liver disease. Using a suite of genome-wide genetic screens we have recently identified SPRING (C12ORF49) as a novel post-transcriptional regulator of SREBP activation in vitro. Our previous work demonstrated that constitutive ablation of Spring in mice is embryonically lethal. Here we show that inducible global deletion of Spring is also untolerated, and therefore to interrogate the physiological role of SPRING in controlling hepatic lipid metabolism we developed liver-specific Spring knockout mice (LKO). Liver transcriptomics and proteomics analysis revealed severely attenuated SREBP signaling in livers and in hepatocytes of LKO mice, which was associated with marked effects on both plasma and hepatic lipid levels. In plasma, total cholesterol levels were dramatically reduced in both male and female LKO mice, apparent in both the LDL and HDL fractions, while triglyceride levels remained largely unaffected. In liver, loss of Spring diminished cholesterol and triglyceride biosynthesis resulting in decreased hepatic cholesterol and triglyceride content. This coincided with reduced secretion of VLDL into the circulation. Consistent with diminished hepatic de novo lipogenesis, LKO mice were protected from developing hepatosteatosis when challenged with a fructose-rich diet. Supporting the significance of our findings in mice, we identified common and rare SPRING genetic variants that are strongly associated with circulating HDL-c and ApoA1 levels in humans. Collectively, our study positions SPRING as a core component of hepatic SREBP signaling, and consequently of systemic lipid metabolism in mice and humans.

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Hepatic phosphorylation of transcription factor SREBP-1a interferes with gene regulation and peroxisomal function

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