Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Altered de novo lipogenesis contributes to low adipose stores in cystic fibrosis mice.

ABSTRACT: Cystic fibrosis (CF) mouse models exhibit exocrine pancreatic function yet do not develop adipose stores to the levels of non-CF mice. CF mice homozygous for the Cftr mutation (F508del) at 3 weeks (post-weaning) and 6 weeks (young adult) of age had markedly less adipose tissue than non-CF mice. Both 3- and 6-week old mice had dietary lipid absorption and fecal lipid excretion comparable to non-CF controls. Fractional hepatic de novo synthesis of palmitate and stearate (de novo lipogenesis, DNL) as determined by deuterium incorporation was reduced in CF mice. At 3 weeks of age, F508del mice had significantly decreased DNL of palmitate and stearate, by 83% and 80%, respectively. By 6 weeks of age, DNL rates in non-CF mice remained unchanged as compared to 3-week old mice, while DNL rates of F508del mice were still reduced, by 33% and 40%, respectively. Adipose tissue fatty acid profiles were comparable in CF and non-CF mice, indicating that adipose differences are quantitative, not qualitative. A correspondingly lower content of deuterium-labeled fatty acids was found in CF adipose tissue, consistent with reduced deposition of newly made hepatic triglycerides and/or decreased adipose tissue lipogenesis. Hepatic transcriptome analysis revealed lower mRNA expression from several genes involved in fatty acid biosynthesis, suggesting down-regulation of several enzymes in fatty acids synthesis as a mechanism for the reduced lipogenesis. These novel data provide a model for altered fat and fatty acid metabolism in CF, independent of malabsorption, and may partly explain the inability of pancreatic enzyme replacement therapy to completely restore normal body mass to CF patients ∆F508 CF mice and its WT littermates (3-weeks old females, C57BL/6J) were examined. RNA extracted from snapped-frozen livers, 4 replicates per genotype.

ORGANISM(S): Mus musculus

SUBMITTER: Aura Perez

PROVIDER: E-GEOD-33319 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Publications

Altered de novo lipogenesis contributes to low adipose stores in cystic fibrosis mice.

Bederman Ilya I Perez Aura A Henderson Leigh L Freedman Joshua A JA Poleman James J Guentert Dana D Ruhrkraut Nicholas N Drumm Mitchell L ML

American journal of physiology. Gastrointestinal and liver physiology 20120607 4

Cystic fibrosis (CF) mouse models exhibit exocrine pancreatic function, yet they do not develop adipose stores to the levels of non-CF mice. CF mice homozygous for the Cftr mutation (F508del) at 3 wk (postweaning) and 6 wk (young adult) of age had markedly less adipose tissue than non-CF mice. Food intake was markedly lower in 3-wk-old CF mice but normalized by 6 wk of age. Both 3- and 6-wk-old mice had dietary lipid absorption and fecal lipid excretion comparable to non-CF mice. Hepatic de novo ...[more]

PMID: 22679004

Similar Datasets

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.

Dataset Information

Altered de novo lipogenesis contributes to low adipose stores in cystic fibrosis mice.

Publications

Altered de novo lipogenesis contributes to low adipose stores in cystic fibrosis mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure