Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Gene expression profiling of livers from cafestol-fed APOE3Leiden mice

ABSTRACT: Unfiltered coffee markedly increases serum lipid levels in humans and mice. The responsible compounds are the fat-soluble diterpenes cafestol and kahweol. Cafestol is responsible for more than 80% of the effect on serum lipids and is the most potent cholesterol-elevating compound known in the human diet. Aim of these microarray studies was to identify novel genes and regulatory pathways determining the cholesterol raising effect of cafestol by genome-wide expression studies. Keywords: Transgenic APOE3Leiden_Mouse_liver_diet response_cafestol Transgenic APOE3Leiden (E3L) mice of the N21th generation (>99% C57BL6/JIco) were used. Mice were 10 weeks of age at the start of experiments, and received control or cafestol diet for 4 weeks (n=7 and 8 respectively). As control diet, diet W (Hope Farms) was used, a semi-synthetic diet (18.2 MJ/kg) enriched with saturated fat (15g/100g) and cholesterol (0.25g/100g). This diet was supplemented with 0.04% (wt/wt) cafestol and 0.02% (wt/wt) kahweol for the cafestol diet. Microarray experiments were performed in duplicate: the same RNAs were labeled, divided into two different pools and hybridized onto two different GEMs 2.03 (Incyte Genomics, Palo Alto, CA). Duplicates are indicated by the same SY or TP number in the sample titles.

ORGANISM(S): Mus musculus

SUBMITTER: Marten H. Hofker

PROVIDER: E-GEOD-3809 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors.

Ricketts Marie-Louise ML Boekschoten Mark V MV Kreeft Arja J AJ Hooiveld Guido J E J GJ Moen Corina J A CJ Müller Michael M Frants Rune R RR Kasanmoentalib Soemini S Post Sabine M SM Princen Hans M G HM Porter J Gordon JG Katan Martijn B MB Hofker Marten H MH Moore David D DD

Molecular endocrinology (Baltimore, Md.) 20070424 7

Cafestol, a diterpene present in unfiltered coffee brews such as Scandinavian boiled, Turkish, and cafetière coffee, is the most potent cholesterol-elevating compound known in the human diet. Several genes involved in cholesterol homeostasis have previously been shown to be targets of cafestol, including cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid biosynthesis. We have examined the mechanism by which cafestol elevates serum lipid levels. Changes in several lipi ...[more]

PMID: 17456796

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Project description:Paneth cells of intestinal crypts contribute to host defense by producing antimicrobial peptides that are packaged as granules for secretion into the crypt lumen. Here, we provide evidence using light and electron microscopy that postsecretory Paneth cell granules undergo limited dissolution and accumulate within the intestinal crypts of cystic fibrosis (CF) mice. On the basis of this finding, we evaluated bacterial colonization and expression of two major constituents of Paneth cells, i.e., {alpha}-defensins (cryptdins) and lysozyme, in CF murine intestine. Paneth cell granules accumulated in intestinal crypt lumens in both untreated CF mice with impending intestinal obstruction and in CF mice treated with an osmotic laxative that prevented overt clinical symptoms and mucus accretion. Ultrastructure studies indicated little change in granule morphology within mucus casts, whereas granules in laxative-treated mice appear to undergo limited dissolution. Protein extracts from CF intestine had increased levels of processed cryptdins compared with those from wild-type (WT) littermates. Nonetheless, colonization with aerobic bacteria species was not diminished in the CF intestine and oral challenge with a cryptdin-sensitive enteric pathogen, Salmonella typhimurium, resulted in greater colonization of CF compared with WT intestine. Modest downregulation of cryptdin and lysozyme mRNA in CF intestine was shown by microarray analysis, real-time quantitative PCR, and Northern blot analysis. Based on these findings, we conclude that antimicrobial peptide activity in CF mouse intestine is compromised by inadequate dissolution of Paneth cell granules within the crypt lumens. Total RNA was extracted from pooled small intestines of three WT and three CF mice using Tri-Reagent (Molecular Research Center, Cincinnati, OH), and poly(A) RNA was purified by using the MicroPoly(A) mRNA purification kit (Ambion, Austin, TX). The WT and CF poly(A) RNA samples were sent to IncyteGenomics (St. Louis, MO) where they were labeled with cyanine 3 (Cy3) and Cy5, respectively, and hybridized with the UniGEM1.31 array representing 9,570 known genes and expressed sequence tags.

Project description:Background: Genetic elimination of c-Met signaling in the liver has been shown to impact many cellular pathways involved in repair, regeneration, lipid homeostasis and redox balance. In this study, we analyzed a nutritional model of hepatic steatosis in Met fl/fl ; Alb-Cre +/- (MetKO) mice in a 129SV/C57BL/6 background fed a high cholesterol diet for 30 days. Methods: Liver injury was determined by histopathology and plasma enzymes, transcriptomic changes were examined using gene expression microarrays, and evaluation of key molecules involved in liver damage and lipid homestasis were evaluated by Western blot analysis. Results: We observed that in comparison with wild type mice subjected to the same diet, MetKO mice developed a strong liver lipid deposition, inflammatory infiltration and increment in total bile acids synthesis and liver damage markers. Global transcriptomic changes analysis confirmed the steatosis and cholestasis induced by the high cholesterol diet. In addition, we found affected pathways related to amino acids, glutathione and lipid metabolism, oxidative stress and mitochondria dysfunction. Oxidative stress exacerbation was corroborated by lipid and protein oxidation in liver tissue. To address further, Western blot studies revealed downregulation on Erk, NF-kB and Nrf2 survival pathways and target genes (cyclin D1, SOD1, gamma-GCS), an increment in proapoptotic proteins (p53, caspase 3) and changes in nuclear receptors such as RAR and RXR, which were increased, and CAR, FXR and PPAR alfa, which were decreased, in the MetKO diet. These results are in agreement with the steatosis and cholestasis phenotype. Conclusion: Our data provide evidence of c-Met signaling involvement in lipid metabolism, and bile acids synthesis and excretion. Disruption of these pathways leads to liver dysfunction, improper metabolism and hepatocellular damage. Global transcriptome changes between WT mice vs. c-Met KO mice fed a 2% cholesterol and 0.5% sodium cholate diet (high cholesterol) or a Chow regular diet (Chow) as control. Mice were fed a high cholesterol or chow regular diet for 30 days. Liver tissue was obtained, and RNA was extracted and subjected to Illumina microarray analysis.

Dataset Information

Gene expression profiling of livers from cafestol-fed APOE3Leiden mice

Publications

The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors.

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