Genome-wide hepatic DNA methylation changes in high-fat diet-induced obese mice
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BACKGROUND/OBJECTIVES: A high-fat diet (HFD) induces obesity, which is a major risk factor for cardiovascular disease and cancer, while a calorie-restricted diet can extend life span by reducing the risk of these diseases. It is known that health effects of diet are partially conveyed through epigenetic mechanism including DNA methylation. In this study, we investigated the genome-wide hepatic DNA methylation to identify the epigenetic effects of HFD-induced obesity. MATERIALS AND METHODS: Seven-week-old male C57BL/6 mice were fed control diet (CD), calorie-restricted control diet (CRCD), or HFD for 16 weeks (after one week of acclimation to the control diet). Food intake, body weight, and liver weight were measured. Hepatic triacylglycerol and cholesterol levels were determined using enzymatic colorimetric methods. Changes in genome-wide DNA methylation were determined by a DNA methylation microarray method combined with methylated DNA immunoprecipitation. The level of transcription of individual genes was measured by real-time PCR. RESULTS: The DNA methylation statuses of genes in biological networks related to lipid metabolism and hepatic steatosis were influenced by HFD-induced obesity. In HFD group, a proinflammatory Casp1 (Caspase 1) gene had hypomethylated CpG sites at the 1.5-kb upstream region of its transcription start site (TSS), and its mRNA level was higher compared with that in CD group. Additionally, an energy metabolism-associated gene Ndufb9 (NADH dehydrogenase 1 beta subcomplex 9) in HFD group had hypermethylated CpG sites at the 2.6-kb downstream region of its TSS, and its mRNA level was lower compared with that in CRCD group. CONCLUSIONS: HFD alters DNA methylation profiles in genes associated with liver lipid metabolism and hepatic steatosis. The methylation statuses of Casp1 and Ndufb9 were particularly influenced by the HFD. The expression of these genes in HFD differed significantly compared with CD and CRCD, respectively, suggesting that the expressions of Casp1 and Ndufb9 in liver were regulated by their methylation statuses.
Abstract
BACKGROUND/OBJECTIVES: A high-fat diet (HFD) induces obesity, which is a major risk factor for cardiovascular disease and cancer, while a calorie-restricted diet can extend life span by reducing the risk of these diseases. It is known that health effects of diet are partially conveyed through epigenetic mechanism including DNA methylation. In this study, we investigated the genome-wide hepatic DNA methylation to identify the epigenetic effects of HFD-induced obesity. MATERIALS AND METHODS: Seven-week-old male C57BL/6 mice were fed control diet (CD), calorie-restricted control diet (CRCD), or HFD for 16 weeks (after one week of acclimation to the control diet). Food intake, body weight, and liver weight were measured. Hepatic triacylglycerol and cholesterol levels were determined using enzymatic colorimetric methods. Changes in genome-wide DNA methylation were determined by a DNA methylation microarray method combined with methylated DNA immunoprecipitation. The level of transcription of individual genes was measured by real-time PCR. RESULTS: The DNA methylation statuses of genes in biological networks related to lipid metabolism and hepatic steatosis were influenced by HFD-induced obesity. In HFD group, a proinflammatory Casp1 (Caspase 1) gene had hypomethylated CpG sites at the 1.5-kb upstream region of its transcription start site (TSS), and its mRNA level was higher compared with that in CD group. Additionally, an energy metabolism-associated gene Ndufb9 (NADH dehydrogenase 1 beta subcomplex 9) in HFD group had hypermethylated CpG sites at the 2.6-kb downstream region of its TSS, and its mRNA level was lower compared with that in CRCD group. CONCLUSIONS: HFD alters DNA methylation profiles in genes associated with liver lipid metabolism and hepatic steatosis. The methylation statuses of Casp1 and Ndufb9 were particularly influenced by the HFD. The expression of these genes in HFD differed significantly compared with CD and CRCD, respectively, suggesting that the expressions of Casp1 and Ndufb9 in liver were regulated by their methylation statuses.
참고문헌 (32)
- Lim SS, "A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010", Lancet, 380, pp.2224~2260 (2012)
- Eckel RH, "The metabolic syndrome", Lancet, 365, pp.1415~1428 (2005)
- Seppälä-Lindroos A, "Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men", J Clin Endocrinol Metab, 87, pp.3023~3028 (2002)
- Kotronen A, "Liver fat in the metabolic syndrome", J Clin Endocrinol Metab, 92, pp.3490~3497 (2007)
- Ridker PM, "C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women", Circulation, 107, pp.391~397 (2003)
- Mertens I, "Among inflammation and coagulation markers, PAI-1is a true component of the metabolic syndrome", Int J Obes, 30, pp.1308~1314 (2006)
- Park EJ, "Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression", Cell, 140, pp.197~208 (2010)
- Choi SW, "Epigenetics: a new bridge between nutrition and health", Adv Nutr, 1, pp.8~16 (2010)
- Milagro FI, "High fat diet-induced obesity modifies the methylation pattern of leptin promoter in rats", J Physiol Biochem, 65, pp.1~9 (2009)
- Jiang M, "Hypermethylation of hepatic glucokinase and L-type pyruvate kinase promoters in high-fat diet-induced obese rats", Endocrinology, 152, pp.1284~1289 (2011)
- Schwenk RW, "Diet-dependent alterations of hepatic Scd1 expression are accompanied by differences in promoter methylation", Horm Metab Res, 45, pp.786~794 (2013)
- Chang X, "Berberine reduces methylation of the MTTP promoter and alleviates fatty liver induced by a high-fat diet in rats", J Lipid Res, 51, pp.2504~2515 (2010)
- Dudley KJ, "Offspring of mothers fed a high fat diet display hepatic cell cycle inhibition and associated changes in gene expression and DNA methylation", PLoS One, 6, pp.e21662~ (2011)
- Zhang Y, "High-fat diet caused widespread epigenomic differences on hepatic methylome in rat", Physiol Genomics, 47, pp.514~523 (2015)
- Richardson B., "Impact of aging on DNA methylation", Ageing Res Rev, 2, pp.245~261 (2003)
- Folch J, "A simple method for the isolation and purification of total lipides from animal tissues", J Biol Chem, 226, pp.497~509 (1957)
- Jin SG, "Examination of the specificity of DNA methylation profiling techniques towards 5-methylcytosine and 5-hydroxymethylcytosine", Nucleic Acids Res, 38, pp.e125~ (2010)
- Irizarry RA, "Comprehensive high-throughput arrays for relative methylation (CHARM)", Genome Res, 18, pp.780~790 (2008)
- Tammen SA, "Hepatic DNA hydroxymethylation is site-specifically altered by chronic alcohol consumption and aging", Eur J Nutr. Forthcoming (2015)
- McLean CY, "GREAT improves functional interpretation of cis-regulatory regions", Nat Biotechnol, 28, pp.495~501 (2010)
- Fujita PA, "The UCSC Genome Browser database: update 2011", Nucleic Acids Res, 39, pp.D876~D882 (2011)
- Livak KJ, "Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method", Methods, 25, pp.402~408 (2001)
- Franchi L, "The inflammasome:a caspase-1-activation platform that regulates immune responses and disease pathogenesis", Nat Immunol, 10, pp.241~247 (2009)
- Smeitink J, "Human mitochondrial complex I in health and disease", Am J Hum Genet, 64, pp.1505~1510 (1999)
- Haack TB, "Mutation screening of 75 candidate genes in 152 complex I deficiency cases identifies pathogenic variants in 16 genes including NDUFB9", J Med Genet, 49, pp.83~89 (2012)
- Jones PA, "Functions of DNA methylation: islands, start sites, gene bodies and beyond", Nat Rev Genet, 13, pp.484~492 (2012)
- Ge ZJ, "DNA methylation in oocytes and liver of female mice and their offspring: effects of high-fat-diet-induced obesity", Environ Health Perspect, 122, pp.159~164 (2014)
- Murphy SK, "Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease", Gastroenterology, 145, pp.1076~1087 (2013)
- Choi MS, "High-fat diet decreases energy expenditure and expression of genes controlling lipid metabolism, mitochondrial function and skeletal system development in the adipose tissue, along with increased expression of extracellular matrix remodelling- and inflammation-related genes", Br J Nutr, 113, pp.867~877 (2015)
- Jones PA, "The DNA methylation paradox", Trends Genet, 15, pp.34~37 (1999)
- Lorincz MC, "Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells", Nat Struct Mol Biol, 11, pp.1068~1075 (2004)
- National Research Council (US) Subcommittee on Laboratory Animal Nutrition, "Nutrient Requirements of Laboratory Animals" (1995), National Academies Press