Animal Bioscience

Asian Australasian Association of Animal Production Societies (아세아태평양축산학회)
권호 표지
DOI QR코드

DOI QR Code

Parental betaine supplementation promotes hepatic conversion of cholesterol to bile acids in offspring goslings with epigenetic modulation of CYP7A1 gene

  • Shuai Ma (Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University) ;
  • Liang Chen (Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University) ;
  • Yan Wang (Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University) ;
  • Lei Wu (Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University) ;
  • Ruqian Zhao (Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University)
  • Received : 2024.12.06
  • Accepted : 2025.03.17
  • Published : 2025.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

Objective: Maternal betaine supplementation has been shown to affect offspring metabolism through epigenetic mechanisms in mammals. This study aimed to investigate whether parental betaine supplementation can exert intergenerational effects on hepatic cholesterol metabolism in offspring goslings, and the possible epigenetic modification associated with such effects. Methods: In this study, 450 female and 90 male Jiangnan White goose breeders, aged 39 weeks, were randomly assigned to three groups receiving basal (control, CON), or betaine-supplemented diets at low (LBT, 2.5 g/kg) or high (HBT, 5 g/kg) levels for 7 weeks. The breeder eggs laid in the last week were collected for incubation. Offspring goslings were slaughtered at 35 and 63 days of age to collect blood, bile, and liver samples for biochemical analysis and gene and protein expression studies. Results: The body weight of goslings in the LBT and HBT groups was significantly higher than that in the CON group (p<0.05). Serum and liver total cholesterol contents were significantly decreased in the HBT group (p<0.05), while the total bile acids contents in the liver and bile were significantly increased (p<0.05). These changes were associated with the upregulation of cholesterol-7 alpha-hydroxylase (CYP7A1) and bile salt export protein at both mRNA and protein levels (p<0.05). Additionally, parental betaine supplementation significantly decreased the DNA methylation level on the promoter region of the CYP7A1 gene (p<0.05). Conclusion: These results indicate that parental betaine supplementation decreases hepatic cholesterol content in offspring goslings through epigenetic modulation of the CYP7A1 gene.

Keywords

Acknowledgement

This work was supported by the National Key Research and Development Program of China (2022YFD1300401), the National Natural Science Foundation of China (32272962, 31972638).

References

  1. Luo J, Yang H, Song BL. Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Biol 2020;21:225-45. https://doi.org/10.1038/s41580-019-0190-7
  2. Chiang JYL. Bile acid metabolism and signaling. Compr Physiol 2013;3:1191-212. https://doi.org/10.1002/j.2040-4603.2013.tb00517.x
  3. Bays HE, Kirkpatrick CF, Maki KC, et al. Obesity, dyslipidemia, and cardiovascular disease: a joint expert review from the obesity medicine association and the national lipid association 2024. J Clin Lipidol 2024;18:e320-50. https://doi.org/10.1016/j.jacl.2024.04.001
  4. Bal NC, Maurya SK, Singh S, Wehrens XHT, Periasamy M. Increased reliance on muscle-based thermogenesis upon acute minimization of brown adipose tissue function. J Biol Chem 2016;291:17247-57. https://doi.org/10.1074/jbc.M116.728188 
  5. Attia YA, Al-Harthi MA, Korish MA, Shiboob MM. Fatty acid and cholesterol profiles, hypocholesterolemic, atherogenic, and thrombogenic indices of broiler meat in the retail market. Lipids Health Dis 2017;16:40. https://doi.org/10.1186/s12944-017-0423-8
  6. Idriss AA, Hu Y, Sun Q, et al. Prenatal betaine exposure modulates hypothalamic expression of cholesterol metabolic genes in cockerels through modifications of DNA methylation. Poult Sci 2017;96:1715-24. https://doi.org/10.3382/ps/pew437
  7. Polin D, Wolford JH. Role of estrogen as a cause of fatty liver hemorrhagic syndrome. J Nutr 1977;107:873-86. https://doi.org/10.1093/jn/107.5.873
  8. Li T, Chiang JYL. Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev 2014;66:948-83. https://doi.org/10.1124/pr.113.008201
  9. Perino A, Schoonjans K. Metabolic messengers: bile acids. Nat Metab 2022;4:416-23. https://doi.org/10.1038/s42255-022-00559-z
  10. Alrefai WA, Gill RK. Bile acid transporters: structure, function, regulation and pathophysiological implications. Pharm Res 2007;24:1803-23. https://doi.org/10.1007/s11095-007-9289-1
  11. Goharkhay N, Tamayo EH, Yin H, Hankins GDV, Saade GR, Longo M. Maternal hypercholesterolemia leads to activation of endogenous cholesterol synthesis in the offspring. Am J Obstet Gynecol 2008;199:273.e1-6. https://doi.org/10.1016/j.ajog.2008.06.064
  12. Sohi G, Marchand K, Revesz A, Arany E, Hardy DB. Maternal protein restriction elevates cholesterol in adult rat offspring due to repressive changes in histone modifications at the cholesterol 7α-hydroxylase promoter. Mol Endocrinol 2011;25:785-98. https://doi.org/10.1210/me.2010-0395
  13. Cong R, Jia Y, Li R, et al. Maternal low-protein diet causes epigenetic deregulation of HMGCR and CYP7α1 in the liver of weaning piglets. J Nutr Biochem 2012;23:1647-54. https://doi.org/10.1016/j.jnutbio.2011.11.007
  14. del Bas JM, Crescenti A, Arola-Arnal A, Oms-Oliu G, Arola L, Caimari A. Intake of grape procyanidins during gestation and lactation impairs reverse cholesterol transport and increases atherogenic risk indexes in adult offspring. J Nutr Biochem 2015;26:1670-7. https://doi.org/10.1016/j.jnutbio.2015.08.015
  15. Mahmoud AM, Ali MM. Methyl donor micronutrients that modify DNA methylation and cancer outcome. Nutrients 2019;11:608. https://doi.org/10.3390/nu11030608
  16. Wen C, Chen R, Chen Y, Ding L, Wang T, Zhou Y. Betaine improves growth performance, liver health, antioxidant status, breast meat yield, and quality in broilers fed a mold-contaminated corn-based diet. Anim Nutr 2021;7:661-6. https://doi.org/10.1016/j.aninu.2020.11.014
  17. Chen R, Zhuang S, Chen YP, Cheng YF, Wen C, Zhou YM. Betaine improves the growth performance and muscle growth of partridge shank broiler chickens via altering myogenic gene expression and insulin-like growth factor-1 signaling pathway. Poult Sci 2018;97:4297-305. https://doi.org/10.3382/ps/pey303
  18. Park SO, Kim WK. Effects of betaine on biological functions in meat-type ducks exposed to heat stress. Poult Sci 2017;96:1515. https://doi.org/10.3382/ps/pew416
  19. Saeed M, Babazadeh D, Naveed M, Arain MA, Hassan FU, Chao S. Reconsidering betaine as a natural anti-heat stress agent in poultry industry: a review. Trop Anim Health Prod 2017;49:1329-38. https://doi.org/10.1007/s11250-017-1355-z
  20. Yang Z, Asare E, Yang Y, Yang JJ, Yang HM, Wang ZY. Dietary supplementation of betaine promotes lipolysis by regulating fatty acid metabolism in geese. Poult Sci 2021;100:101460. https://doi.org/10.1016/j.psj.2021.101460
  21. Hu Y, Feng Y, Ding Z, et al. Maternal betaine supplementation decreases hepatic cholesterol deposition in chicken offspring with epigenetic modulation of SREBP2 and CYP7A1 genes. Poult Sci 2020;99:3770. https://doi.org/10.1016/j.psj.2020.06.002
  22. Ma S, Wang Y, Chen L, et al. Parental betaine supplementation promotes gosling growth with epigenetic modulation of IGF gene family in the liver. J Anim Sci 2024;102:skae065. https://doi.org/10.1093/jas/skae065
  23. He Q, Zou T, Chen J, et al. Maternal methyl-donor micronutrient supplementation during pregnancy promotes skeletal muscle differentiation and maturity in newborn and weaning pigs. Front Nutr 2020;7:609022. https://doi.org/10.3389/fnut.2020.609022
  24. Cai D, Jia Y, Lu J, et al. Maternal dietary betaine supplementation modifies hepatic expression of cholesterol metabolic genes via epigenetic mechanisms in newborn piglets. Br J Nutr 2014;112:1459-68. https://doi.org/10.1017/S0007114514002402
  25. Sun L, Tan X, Liang X, et al. Maternal betaine supplementation mitigates maternal high fat diet-induced NAFLD in offspring mice through gut microbiota. Nutrients 2023;15:284. https://doi.org/10.3390/nu15020284
  26. Zhao N, Yang S, Hu Y, Dong H, Zhao R. Maternal betaine supplementation in rats induces intergenerational changes in hepatic IGF-1 expression and DNA methylation. Mol Nutr Food Res 2017;61:1600940. https://doi.org/10.1002/mnfr.201600940
  27. Lillycrop KA, Burdge GC. Epigenetic mechanisms linking early nutrition to long term health. Best Pract Res Clin Endocrinol Metab 2012;26:667-76. https://doi.org/10.1016/j.beem.2012.03.009
  28. Day CR, Kempson SA. Betaine chemistry, roles, and potential use in liver disease. Biochim Biophys Acta Gen Subj 2016;1860:1098-106. https://doi.org/10.1016/j.bbagen.2016.02.001
  29. Zhao N, Yang S, Feng Y, Sun B, Zhao R. Enhanced hepatic cholesterol accumulation induced by maternal betaine exposure is associated with hypermethylation of CYP7A1 gene promoter. Endocrine 2019;64:544-51. https://doi.org/10.1007/s12020-019-01906-z
  30. Li X, Sun Q, Li X, et al. Dietary betaine supplementation to gestational sows enhances hippocampal IGF2 expression in newborn piglets with modified DNA methylation of the differentially methylated regions. Eur J Nutr 2015;54:1201-10. https://doi.org/10.1007/s00394-014-0799-4
  31. Sato M, Sato K, Furuse M. Change in hepatic and plasma bile acid contents and its regulatory gene expression in the chicken embryo. Comp Biochem Physiol B Biochem Mol Biol 2008;150:344-7. https://doi.org/10.1016/j.cbpb.2008.04.003
  32. Ma S, Liu J, Zhao Y, Wang Y, Zhao R. In ovo betaine injection improves breast muscle growth in newly hatched goslings through FXR/IGF-2 pathway. Poult Sci 2024;103:104075. https://doi.org/10.1016/j.psj.2024.104075
  33. Matthews JO, Southern LL, Higbie AD, Persica MA, Bidner TD. Effects of betaine on growth, carcass characteristics, pork quality, and plasma metabolites of finishing pigs. J Anim Sci 2001;79:722-8. https://doi.org/10.2527/2001.793722x
  34. Albuquerque A, Neves JA, Redondeiro M, et al. Long term betaine supplementation regulates genes involved in lipid and cholesterol metabolism of two muscles from an obese pig breed. Meat Sci 2017;124:25-33. https://doi.org/10.1016/j.meatsci.2016.10.012
  35. Wu Y, Zhang M, Meng F, et al. Betaine supplementation alleviates corticosterone-induced hepatic cholesterol accumulation through epigenetic modulation of HMGCR and CYP7A1 genes in laying hens. Poult Sci 2024;103:103435. https://doi.org/10.1016/j.psj.2024.103435
  36. Wang F, Xu J, Jakovlić I, Wang WM, Zhao YH. Dietary betaine reduces liver lipid accumulation via improvement of bile acid and trimethylamine-N-oxide metabolism in bluntsnout bream. Food Funct 2019;10:6675-89. https://doi.org/10.1039/C9FO01853K
  37. Wang C, Liu X, Sun X, Li Y, Yang X, Liu Y. Dietary betaine supplementation improved egg quality and gut microbes of laying hens under dexamethasone-induced oxidative stress. Poult Sci 2024;103:104178. https://doi.org/10.1016/j.psj.2024.104178
  38. Zaki A, Jiang S, Zaghloul S, et al. Betaine as an alternative feed additive to choline and its effect on performance, blood parameters, and egg quality in laying hens rations. Poult Sci 2023;102:102710. https://doi.org/10.1016/j.psj.2023.102710
  39. Li Y, Jiang W, Feng Y, Wu L, Jia Y, Zhao R. Betaine alleviates high-fat diet-induced disruption of hepatic lipid and iron homeostasis in mice. Int J Mol Sci 2022;23:6263. https://doi.org/10.3390/ijms23116263
  40. Zhao G, He F, Wu C, et al. Betaine in inflammation: mechanistic aspects and applications. Front Immunol 2018;9:1070. https://doi.org/10.3389/fimmu.2018.01070
  41. Ratriyanto A, Mosenthin R. Osmoregulatory function of betaine in alleviating heat stress in poultry. J Anim Physiol Anim Nutr 2018;102:1634-50. https://doi.org/10.1111/jpn.12990
  42. Yang W, Huang L, Gao J, et al. Betaine attenuates chronic alcohol induced fatty liver by broadly regulating hepatic lipid metabolism. Mol Med Rep 2017;16:5225-34. https://doi.org/10.3892/mmr.2017.7295
  43. Chiang JYL. Bile acids: regulation of synthesis. J Lipid Res 2009;50:1955-66. https://doi.org/10.1194/jlr.R900010-JLR200
  44. Shin DJ, Wang L. Bile acid-activated receptors: a review on FXR and other nuclear receptors. Handb Exp Pharmacol 2019;256:51-72. https://doi.org/10.1007/164_2019_236
  45. Kerr TA, Saeki S, Schneider M, et al. Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis. Dev Cell 2002;2:713-20. https://doi.org/10.1016/s1534-5807(02)00154-5
  46. Li S, Xu S, Zhao Y, Wang H, Feng J. Dietary betaine addition promotes hepatic cholesterol synthesis, bile acid conversion, and export in rats. Nutrients 2020;12:1399. https://doi.org/10.3390/nu12051399
  47. Kalhan SC. One carbon metabolism in pregnancy: impact on maternal, fetal and neonatal health. Mol Cell Endocrinol 2016;435:48-60. https://doi.org/10.1016/j.mce.2016.06.006
  48. Cordero P, Gomez-Uriz AM, Campion J, Milagro FI, Martinez JA. Dietary supplementation with methyl donors reduces fatty liver and modifies the fatty acid synthase DNA methylation profile in rats fed an obesogenic diet. Genes Nutr 2013;8:105-13. https://doi.org/10.1007/s12263-012-0300-z
  49. Kovacheva VP, Mellott TJ, Davison JM, et al. Gestational choline deficiency causes global and Igf2 gene DNA hypermethylation by up-regulation of Dnmt1 expression. J Biol Chem 2007;282:31777-88. https://doi.org/10.1074/jbc.M705539200