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The Effects of Betaine Treatment on Rats Fed an Acute Bolus of Ethanol at 3 and 12 H Post Bolus: a Microarray Analysis

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The Effects of Betaine Treatment on Rats Fed an Acute Bolus of Ethanol at 3 and 12 H Post Bolus: a Microarray Analysis View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central Genes Nutr (2010) 5:321–329 DOI 10.1007/s12263-010-0173-y RESEARCH PAPER The effects of betaine treatment on rats fed an acute bolus of ethanol at 3 and 12 h post bolus: a microarray analysis J. Li • F. Bardag-Gorce • J. Oliva • B. A. French • J. Dedes • S. W. French Received: 24 November 2009 / Accepted: 19 February 2010 / Published online: 19 March 2010 Ó The Author(s) 2010. This article is published with open access at Springerlink.com Abstract Betaine, a methyl donor active in methionine Introduction metabolism, is effective in preventing and reversing experimental alcohol liver disease. The metabolic and Ethanol, given as a bolus of 6 g/kg body weight, increases molecular biologic mechanisms involved in this prevention the blood and urinary alcohol to a high level at 3 h post are only partially known. To further investigate how betaine bolus. At 12 h, the blood and urinary alcohol levels return modifies the effects of ethanol on the liver, rats were given to low a level [2]. At these 2 time points, there are major an acute ethanol bolus with or without betaine and the changes in gene expression in the liver but only minimal results were compared to isocaloric dextrose-fed controls. evidence of epigenetic changes [2]. Only at 12 h is there a Livers were subjected to microarray analysis, and functional decrease in global DNA methylation [2]. pathways and individual gene expression changes were Previously, in using this model, S-adenosylmethionine analyzed. Experimental groups were compared by Venn (SAMe) a major methyl donor was fed with ethanol to diagrams showing that both ethanol and betaine caused a blunt the effects of ethanol on global gene expression [3]. change in the expression of a large number of genes indi- The effects of betaine on gene expression changes induced cating that the changes were global. The bio-informatic by ethanol resembled the effects of SAMe [3]. To further analysis showed that all the KEGG functional pathways test the role that methyl donors have on the changes in gene were affected and mainly down regulated at 3 h post bolus expression in the liver after an acute bolus of ethanol, the when ethanol plus betaine were compared with ethanol-fed methyl donor betaine was fed with ethanol. Theoretically, rats. The most profound effect of betaine was on the meta- the methylation of DNA and histones that occur by feeding bolic pathways both at 3 and 12 h post bolus. At 3 h, the a methyl donor such as betaine could prevent the changes changes in gene expression were mostly down regulated, but in gene expression observed after an ethanol bolus by at 12 h, the changes were regulated equally up and down. causing gene silencing. In the drug-induced liver disease This hypothesis-driven analysis showed that the effects of mouse model, betaine feeding prevented the liver pathol- betaine on the effects of ethanol were partly transient. ogy from developing when the drug was refed [9]. In this mouse model, betaine feeding prevented the changes in Keywords Global change Á Gene expression Á gene expression and the alterations in methionine metab- Methyl donor Á Binge drinking Á Alcohol olism by preventing a decrease in betaine homocysteine methyl transferase (BHMT) and glycine N methyl trans- ferase [9]. Betaine also prevented the decrease in S-ade- J. Li Á F. Bardag-Gorce Á J. Oliva Á B. A. French Á nosylthomocysteine (SAH) [9]. S. W. French (&) Department of Pathology, Harbor-UCLA Medical Center, Betaine feeding is also effective in ameliorating exper- 1000 W. Carson St., Torrance, Los Angeles, CA 90509, USA imental alcoholic fatty liver in rats [1] and mice [4]. In e-mail: [email protected] mice fed ethanol acutely (three boluses of alcohol), betaine given prior to feeding alcohol, alleviated the liver injury J. Dedes LA BioMed, Harbor-UCLA Medical Center, and the impairment of metabolomics [8]. Reduction in 1124 W. Carson St., Torrance, Los Angeles, CA 90502, USA S-adenosylmethionine (SAMe) and glutathione (GSH) was 123 322 Genes Nutr (2010) 5:321–329 prevented, and elevated hypotaurine and taurine were Table 1 UAL, BAL, alanine aminotransferase (ALT) were deter- reduced [8]. Proteomic studies have revealed that betaine mined for 3 and 12 h feeding of alcohol with or without betaine supplements given to ethanol-fed rats up regulated methi- (mean ± SD, n = 3–4) onine metabolic pathway enzymes and down regulated Groups Time (h) N UAL mg % BAL mg % ALT U/l carbonic anhydrase III [5]. Betaine, like SAMe in vitro, Alcohol* 3 4 453 ± 57 347 ± 68 51 ± 3 prevented the shift in the SAMe/SAH ratio that developed Dextrose* 3 4 0 0 41 ± 3 in primary liver cultures from rats fed ethanol [6]. Betaine, Alcohol* 12 3 33 ± 15 29 ± 17 54 ± 3 by supporting the methylation of homocysteine, removes Dextrose* 12 3 0 0 50 ± 4 both homocysteine and SAH, restores SAMe levels to Alcohol ? betaine 3 3 255 ± 130 155 ± 110 60 ± 33 normal, prevents and reverses fatty liver, prevents apop- tosis and reduces damaged proteins and oxidative stress, all Betaine 3 3 0 0 40 ± 3 induced by ethanol ingestion [7, 10]. Alcohol ? betaine 12 3 58 ± 29 41 ± 33 43 ± 8 Betaine 12 3 0 0 51 ± 3 Note that betaine reduced the 3 h blood alcohol levels. The 3-h ALT Methods levels were not different compared to the dextrose controls. The alcohol ? dextrose-treated results (*) were reprinted from Bardag- Gorce et al. [2], with permission from WILEY InterScience Animal model of alcoholic liver disease Male Wistar rats from Harleco (Hollister, CA, USA), FastPrep centrifuge (MP Biomedicals LLC, Irvine, CA, weighing 250–300 g, were used. The rats used were from a USA) for 30 s and incubating them on ice for 1 min. Total previously reported study [2] (number 3–4/group). They RNA was extracted following the TrizolÒ protocol using were fed acutely a bolus of ethanol by gavage (6 g/kg body chloroform, heavy phase lock gel tubes (Eppendorf, weight, 20% solution). Controls were fed isocaloric glu- Westbury, NY), and isopropanol. RNA quality was con- cose. The rats were killed 3 or 12 h after the alcohol bolus. firmed using Agilent’s 2100 BioAnalyzer (Santa Clara, A second group of rats was fed betaine 1 g/kg body weight CA, USA). by gavage with or without ethanol (6 g/kg) or isocaloric About 5 lg of total RNA was used for preparing biotin- dextrose, and killed at 3 or 12 h (Table 1). Urine and blood labeled cRNA. Fifteen micrograms of labeled and were collected at kill to measure alcohol levels. Blood ALT fragmented cRNA were subsequently hybridized to Rat levels were also measured. The urine was collected under Genome 230 2.0 Array (Affymetrix, Santa Clara, CA, toluene to prevent evaporation using metabolic cages (one USA). RNA isolation, labeling, and data analysis were rat/cage), and the urinary alcohol level was measured using performed at the Microarray Core at Los Angeles Bio- a QED Saliva Alcohol A 150 test kit STC Technologies, medical Research Institute. Hybridization, washing, stain- (Bethlehem, PA). Blood alcohol and alanine aminotrans- ing, and scanning of the chips were performed at the ferase (ALT) were measured using a chemical analyzer. At Microarray Core at Cedars-Sinai Medical Center. kill under isofluorane anesthesia, the liver was removed and weighed. A portion of the liver was quick frozen and Microarray analysis stored in isopentane in liquid nitrogen, followed by storage at -80°C. Gene microarray analysis was done on RNA Liver tissue taken from the eight experimental groups extracted from the fast frozen tissue. Microarray analysis (three rats per group), and three rats fed ethanol, betaine, or results were obtained and were compared with microarrays dextrose were subjected to microarray analysis. Five done on liver tissue from previously reported studies [2]. micrograms of total RNA was used for preparing biotin- The rats were maintained according to the Guidelines of labeled cRNA. Labeled and fragmented cRNA was sub- Animal Care, as described by the National Academy of sequently hybridized to rat Genome Array (Affymetrix, Sciences and published by the National Institute of Health Santa Clara, CA, USA). Labeling, hybridization, image (1996). scanning, and initial data analysis were performed at the Microarray Core at Los Angeles Biomedical Research RNA extraction Institute. RNA was converted to cDNA using GeneChipÒ One-Cycle cDNA Synthesis Kit (Affymetrix, Santa Clara, Approximately 50–100 lg of frozen liver samples and CA, USA) and then converted to biotinylated cRNA using 1,000 ll of TrizolÒ (InvitrogenTM, Carlsbad, CA, USA) GeneChipÒ IVT Labeling Kit (Affymetrix, Santa Clara, were added to a Bio 101 bead tube containing Lysing CA, USA). The quality of labeled RNA was confirmed Matrix D (MP Biomedicals, LLC, Irvine, CA, USA). Each with the Affymetrix or Test 3 Array (GeneChipÒ Rat tissue was homogenized by processing the tubes in the Exon1.0ST Array [http://www.affymatrix.com]). The 123 Genes Nutr (2010) 5:321–329 323 biotinylated cRNA from all samples was hybridized to minimum signal intensity of 50 of a probe in either or both Affymetrix Rat GeneChip arrays. To perform the hybrid- of the experimental files. ization and staining, a hybridization cocktail was prepared, After generating a list of differentially expressed genes, which included controls of the fragmented cRNA. The downstream analysis was performed. The filtered tran- samples were hybridized in the array at 45°C for 17 h using scripts were clustered in GeneSpring using SOM, K-means, GeneChip Hybridization Oven 640.
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