Betaine supplement alleviates hepatic triglyceride accumulation of apolipoprotein E deficient mice via reducing methylation of peroxisomal proliferator-activated receptor alpha promoter

详细信息    查看全文

• 作者：Lijun Wang (1)
  Li Chen (1)
  Yaozong Tan (1)
  Jun Wei (1)
  Ying Chang (1)
  Tianru Jin (2)
  Huilian Zhu (1)
  
• 关键词：Betaine ; PPAR alpha ; Fatty liver ; DNA methylation
• 刊名：Lipids in Health and Disease
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：12
• 期：1
• 全文大小：280KB
• 参考文献：1. Mehta K, Van Thiel DH, Shah N, Mobarhan S: Nonalcoholic fatty liver disease: pathogenesis and the role of antioxidants. / Nutr Rev 2002,60(9):289-93. CrossRef
  2. Vuppalanchi R, Chalasani N: Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: selected practical issues in their evaluation and management. / Hepatology 2009,49(1):306-17. CrossRef
  3. Targher G, Bertolini L, Padovani R, Rodella S, Zoppini G, Zenari L, Cigolini M, Falezza G, Arcaro G: Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. / Diabetes Care 2006,29(6):1325-330. CrossRef
  4. Kohjima M, Enjoji M, Higuchi N, Kato M, Kotoh K, Yoshimoto T, Fujino T, Yada M, Yada R, Harada N: Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. / Int J Mol Med 2007,20(3):351-58.
  5. Zeisel SH, Mar MH, Howe JC, Holden JM: Concentrations of choline-containing compounds and betaine in common foods. / J Nutr 2003,133(5):1302-307.
  6. Niculescu MD, Craciunescu CN, Zeisel SH: Dietary choline deficiency alters global and gene-specific DNA methylation in the developing hippocampus of mouse fetal brains. / FASEB J 2006,20(1):43-9. CrossRef
  7. Kovacheva VP, Mellott TJ, Davison JM, Wagner N, Lopez-Coviella I, Schnitzler AC, Blusztajn JK: Gestational choline deficiency causes global and Igf2 gene DNA hypermethylation by up-regulation of Dnmt1 expression. / J Biol Chem 2007,282(43):31777-1788. CrossRef
  8. Tryndyak VP, Han T, Muskhelishvili L, Fuscoe JC, Ross SA, Beland FA, Pogribny IP: Coupling global methylation and gene expression profiles reveal key pathophysiological events in liver injury induced by a methyl-deficient diet. / Mol Nutr Food Res 2011,55(3):411-18. CrossRef
  9. Devlin AM, Singh R, Wade RE, Innis SM, Bottiglieri T, Lentz SR: Hypermethylation of Fads2 and altered hepatic fatty acid and phospholipid metabolism in mice with hyperhomocysteinemia. / J Biol Chem 2007,282(51):37082-7090. CrossRef
  10. Craig SA: Betaine in human nutrition. / Am J Clin Nutr 2004,80(3):539-49.
  11. Chang X, Yan H, Fei J, Jiang M, Zhu H, Lu D, Gao X: Berberine reduces methylation of the MTTP promoter and alleviates fatty liver induced by a high-fat diet in rats. / J Lipid Res 2010,51(9):2504-515. CrossRef
  12. Leone TC, Weinheimer CJ, Kelly DP: A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. / Proc Natl Acad Sci U S A 1999,96(13):7473-478. CrossRef
  13. Schwahn BC, Wang XL, Mikael LG, Wu Q, Cohn J, Jiang H, Maclean KN, Rozen R: Betaine supplementation improves the atherogenic risk factor profile in a transgenic mouse model of hyperhomocysteinemia. / Atherosclerosis 2007,195(2):e100-e107. CrossRef
  14. Abdelmalek MF, Angulo P, Jorgensen RA, Sylvestre PB, Lindor KD: Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. / Am J Gastroenterol 2001,96(9):2711-717. CrossRef
  15. Abdelmalek MF, Sanderson SO, Angulo P, Soldevila-Pico C, Liu C, Peter J, Keach J, Cave M, Chen T, McClain CJ: Betaine for nonalcoholic fatty liver disease: results of a randomized placebo-controlled trial. / Hepatology 2009,50(6):1818-826. CrossRef
  16. Xiao HB, Sun ZL, Lu XY, Li DZ, Xu JP, Hu YP: Beneficial effect of 3,4,5,6- tetrahydroxyxanthone on dyslipidemia in apolipoprotein E-deficient mice. / Can J Physiol Pharmacol 2008,86(12):815-26. CrossRef
  17. Lv S, Fan R, Du Y, Hou M, Tang Z, Ling W, Zhu H: Betaine supplementation attenuates atherosclerotic lesion in apolipoprotein E-deficient mice. / Eur J Nutr 2009,48(4):205-12. CrossRef
  18. Song Z, Deaciuc I, Zhou Z, Song M, Chen T, Hill D, McClain CJ: Involvement of AMP-activated protein kinase in beneficial effects of betaine on high-sucrose diet-induced hepatic steatosis. / Am J Physiol Gastrointest Liver Physiol 2007,293(4):G894-G902. CrossRef
  19. Kathirvel E, Chen P, Morgan K, French SW, Morgan TR: Oxidative stress and regulation of anti-oxidant enzymes in cytochrome P4502E1 transgenic mouse model of non-alcoholic fatty liver. / J Gastroenterol Hepatol 2010,25(6):1136-143. CrossRef
  20. Hiltunen MO, Turunen MP, Hakkinen TP, Rutanen J, Hedman M, Makinen K, Turunen AM, Aalto-Setala K, Yla-Herttuala S: DNA hypomethylation and methyltransferase expression in atherosclerotic lesions. / Vasc Med 2002,7(1):5-1. CrossRef
  21. Slow S, Garrow TA: Liver choline dehydrogenase and kidney betaine-homocysteine methyltransferase expression are not affected by methionine or choline intake in growing rats. / J Nutr 2006,136(9):2279-283.
  22. Perrino LA, Pierce SK: Choline dehydrogenase kinetics contribute to glycine betaine regulation differences in chesapeake bay and atlantic oysters. / J Exp Zool 2000,286(3):250-61. CrossRef
  23. Chen NC, Yang F, Capecci LM, Gu Z, Schafer AI, Durante W, Yang XF, Wang H: Regulation of homocysteine metabolism and methylation in human and mouse tissues. / FASEB J 2010,24(8):2804-817. CrossRef
  24. Kharbanda KK, Mailliard ME, Baldwin CR, Beckenhauer HC, Sorrell MF, Tuma DJ: Betaine attenuates alcoholic steatosis by restoring phosphatidylcholine generation via the phosphatidylethanolamine methyltransferase pathway. / J Hepatol 2007,46(2):314-21. CrossRef
  25. Dilger RN, Garrow TA, Baker DH: Betaine can partially spare choline in chicks but only when added to diets containing a minimal level of choline. / J Nutr 2007,137(10):2224-228.
  26. Mensenkamp AR, Van Luyn MJ, Havinga R, Teusink B, Waterman IJ, Mann CJ, Elzinga BM, Verkade HJ, Zammit VA, Havekes LM: The transport of triglycerides through the secretory pathway of hepatocytes is impaired in apolipoprotein E deficient mice. / J Hepatol 2004,40(4):599-06. CrossRef
  27. Holm PI, Ueland PM, Kvalheim G, Lien EA: Determination of choline, betaine, and dimethylglycine in plasma by a high-throughput method based on normal-phase chromatography-tandem mass spectrometry. / Clin Chem 2003,49(2):286-94. CrossRef
  28. Nolin TD, McMenamin ME, Himmelfarb J: Simultaneous determination of total homocysteine, cysteine, cysteinylglycine, and glutathione in human plasma by high-performance liquid chromatography: application to studies of oxidative stress. / J Chromatogr B Analyt Technol Biomed Life Sci 2007,852(1-):554-61.
  29. Lo YM, Wong IH, Zhang J, Tein MS, Ng MH, Hjelm NM: Quantitative analysis of aberrant p16 methylation using real-time quantitative methylation-specific polymerase chain reaction. / Cancer Res 1999,59(16):3899-903.
  30. Folch J, Lees M, Sloan SGH: A simple method for the isolation and purification of total lipids from animal tissues. / J Biol Chem 1957, 226:497-09.
  
• 作者单位：Lijun Wang (1)
  Li Chen (1)
  Yaozong Tan (1)
  Jun Wei (1)
  Ying Chang (1)
  Tianru Jin (2)
  Huilian Zhu (1)
  
  1. Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Sun Yat-Sen University, 74th Zhongshan Road II, Guangzhou, 510080, People’s Republic of China
  2. Department of Medicine and Physiology, University of Toronto, Toronto, Canada
  

文摘

Background Betaine is a methyl donor and has been considered as a lipotropic effect substance. But its mechanism remains unclear. Hepatic steatosis is associated with abnormal expression of genes involved in hepatic lipid metabolism. DNA methylation contributes to the disregulation of gene expression. Here we hypothesized that betaine supplement and subsequent DNA methylation modifications alter the expression of genes that are involved in hepatic lipid metabolism and hence alleviate hepatic triglyceride accumulation. Methods Male wild-type (WT) C57BL/6 mice (n = 6) were fed with the AIN-93 G diet. ApoE ??/em> mice (n = 12), weight-matched with the WT mice, were divided into two groups (n = 6 per group), and fed with the AIN-93 G diet and AIN-93 G supplemented with 2% betaine/100 g diet. Seven weeks after the intervention, mice were sacrificed. Liver betaine, choline, homocysteine concentration were measured by HPLC. Liver oxidants activity and triglyceride level were assessed by ultraviolet spectrophotometry. Finally, hepatic PPAR alpha gene and its target genes expression levels and the methylation status of the PPAR alpha gene were determined. Results ApoE ??/em> mice had higher hepatic triglyceride and lower GSH-Px activity when compared with the WT mice. Betaine intervention reversed triglyceride deposit, enhanced SOD and GSH-Px activity in the liver. Interestingly, mice fed on betaine-supplemented diet showed a dramatic increase of hepatic choline concentration and a decrease of betaine and homocysteine concentration relative to the WT mice and the ApoE ??/em> mice absent with betaine intervention. Expression of PPAR alpha and CPT1 were decreased and expression of FAS was markedly increased in ApoE ??/em> mice. In parallel, PPAR alpha promoter methylation level were slightly increased in ApoE ??/em> mice though without significance. Betaine supplement upregulated expression of PPAR alpha and its target genes (CPT1, CYP2E1) and reversed hypermethylation of PPAR alpha promoter of ApoE ??/em> mice. Furthermore, PPAR alpha methylation was positively correlated with hepatic betaine concentration. Conclusions Our findings indicate that betaine supplement could alleviate hepatic triglyceride accumulation and improve antioxidant capacity by decreasing PPAR alpha promoter methylation and upregulating PPAR alpha and its target genes mRNA expression.