リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

大学・研究所にある論文を検索できる 「妊娠時重度高中性脂肪血症のマウスモデルの構築と分子機構の解明」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

コピーが完了しました

URLをコピーしました

論文の公開元へ論文の公開元へ
書き出し

妊娠時重度高中性脂肪血症のマウスモデルの構築と分子機構の解明

田中, 督記 東京大学 DOI:10.15083/0002005057

2022.06.22

概要

妊娠時は非妊娠時に比べ健常者においても中性脂肪(TG)が 2-3 倍程度上昇するが、遺伝子的素因がある場合では著しい高 TG 血症(HTG)となり、急性膵炎のリスクとなる。しかし現時点では妊娠時 HTG に対する効果的な介入手段は少ない。遺伝子的素因による妊娠時 HTG のモデル動物も確立されてこなかった。我々はこれまでに加齢や高炭水化物食によるHTG には SREBP-1c が必須であることをヒト HTG モデルマウス(apoA-V 欠損マウス) 及びapoA-V;SREBP-1c 両欠損マウスの確立により明らかにした。今回これらのモデルを用いて妊娠時HTG のメカニズムを in vivo で検討した。結果、①apoA-V 欠損マウスは遺伝子的素因をもつヒト妊娠時 HTG のモデルマウスとして有用であること、②野生型マウスは出産直前にTGRL の蓄積をきたし、この変化は apoA-V 欠損マウスでは著明となること、③出産直前の TGRL の蓄積は SREBP-1c に部分的に依存的し、その標的遺伝子として肝臓のACC2, GPAT が関与している可能性があることが明らかになった。SREBP-1c は妊娠時HTG の有効な治療標的となる可能性がある。

この論文で使われている画像

参考文献

1. Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(9):2969-2989. doi:10.1210/jc.2011-3213

2. Surendran RP, Visser ME, Heemelaar S, et al. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. J Intern Med. 2012;272(2):185-196. doi:10.1111/j.1365-2796.2012.02516.x

3. Fåhraeus L, Larsson-Cohn U, Wallentin L. Plasma lipoproteins including high density lipoprotein subfractions during normal pregnancy. Obstet Gynecol. 1985;66(4):468-472.

4. Xie S-L, Chen T-Z, Huang X-L, et al. Genetic Variants Associated with Gestational Hypertriglyceridemia and Pancreatitis. PloS One. 2015;10(6):e0129488. doi:10.1371/journal.pone.0129488

5. Henneman P, Schaap FG, Rensen PCN, van Dijk KW, Smelt AHM. Estrogen induced hypertriglyceridemia in an apolipoprotein AV deficient patient. J Intern Med. 2008;263(1):107-108. doi:10.1111/j.1365-2796.2007.01889.x

6. Dussaillant C, Serrano V, Maiz A, et al. APOA5 Q97X mutation identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family. BMC Med Genet. 2012;13:106. doi:10.1186/1471-2350-13- 106

7. Papadakis EP, Sarigianni M, Mikhailidis DP, Mamopoulos A, Karagiannis V. Acute pancreatitis in pregnancy: an overview. Eur J Obstet Gynecol Reprod Biol. 2011;159(2):261-266. doi:10.1016/j.ejogrb.2011.07.037

8. Russi G. Severe dyslipidemia in pregnancy: The role of therapeutic apheresis. Transfus Apher Sci Off J World Apher Assoc Off J Eur Soc Haemapheresis. 2015;53(3):283-287. doi:10.1016/j.transci.2015.11.008

9. Goldberg AS, Hegele RA. Severe hypertriglyceridemia in pregnancy. J Clin Endocrinol Metab. 2012;97(8):2589-2596. doi:10.1210/jc.2012-1250

10. Herrera E. Lipid metabolism in pregnancy and its consequences in the fetus and newborn. Endocrine. 2002;19(1):43-55. doi:10.1385/ENDO:19:1:43

11. Martin-Hidalgo A, Holm C, Belfrage P, Schotz MC, Herrera E. Lipoprotein lipase and hormone-sensitive lipase activity and mRNA in rat adipose tissue during pregnancy. Am J Physiol. 1994;266(61):E930-935. doi:10.1152/ajpendo.1994.266.6.E930

12. Smith JL, Lear SR, Forte TM, Ko W, Massimi M, Erickson SK. Effect of pregnancy and lactation on lipoprotein and cholesterol metabolism in the rat. J Lipid Res. 1998;39(11):2237-2249.

13. Wasfi I, Weinstein I, Heimberg M. Hepatic metabolism of [1-14C]oleate in pregnancy. Biochim Biophys Acta. 1980;619(3):471-481. doi:10.1016/0005- 2760(80)90099-5

14. Weinstock PH, Bisgaier CL, Aalto-Setälä K, et al. Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes. J Clin Invest. 1995;96(6):2555-2568. doi:10.1172/JCI118319

15. Péterfy M, Ben-Zeev O, Mao HZ, et al. Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia. Nat Genet. 2007;39(12):1483-1487. doi:10.1038/ng.2007.24

16. Sakurai T, Sakurai A, Vaisman BL, et al. Creation of Apolipoprotein C-II (ApoC-II) Mutant Mice and Correction of Their Hypertriglyceridemia with an ApoC-II Mimetic Peptide. J Pharmacol Exp Ther. 2016;356(2):341-353. doi:10.1124/jpet.115.229740

17. Beigneux AP, Davies BSJ, Gin P, et al. Glycosylphosphatidylinositol-anchored high- density lipoprotein-binding protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab. 2007;5(4):279-291. doi:10.1016/j.cmet.2007.02.002

18. Pennacchio LA, Olivier M, Hubacek JA, et al. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science. 2001;294(5540):169-173. doi:10.1126/science.1064852

19. Kluger M, Heeren J, Merkel M. Apoprotein A-V: an important regulator of triglyceride metabolism. J Inherit Metab Dis. 2008;31(2):281-288. doi:10.1007/s10545-008-0863-4

20. Priore Oliva C, Pisciotta L, Li Volti G, et al. Inherited apolipoprotein A-V deficiency in severe hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2005;25(2):411-417. doi:10.1161/01.ATV.0000153087.36428.dd

21. Marçais C, Verges B, Charrière S, et al. Apoa5 Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment. J Clin Invest. 2005;115(10):2862-2869. doi:10.1172/JCI24471

22. Talmud PJ. Rare APOA5 mutations--clinical consequences, metabolic and functional effects: an ENID review. Atherosclerosis. 2007;194(2):287-292. doi:10.1016/j.atherosclerosis.2006.12.010

23. Albers K, Schlein C, Wenner K, et al. Homozygosity for a partial deletion of apoprotein A-V signal peptide results in intracellular missorting of the protein and chylomicronemia in a breast-fed infant. Atherosclerosis. 2014;233(1):97-103. doi:10.1016/j.atherosclerosis.2013.12.009

24. Pullinger CR, Aouizerat BE, Movsesyan I, et al. An apolipoprotein A-V gene SNP is associated with marked hypertriglyceridemia among Asian-American patients. J Lipid Res. 2008;49(8):1846-1854. doi:10.1194/jlr.P800011-JLR200

25. Okazaki H, Goldstein JL, Brown MS, Liang G. LXR-SREBP-1c-phospholipid transfer protein axis controls very low density lipoprotein (VLDL) particle size. J Biol Chem. 2010;285(9):6801-6810. doi:10.1074/jbc.M109.079459

26. Takanashi M, Kimura T, Li C, et al. Critical Role of SREBP-1c Large-VLDL Pathway in Environment-Induced Hypertriglyceridemia of Apo AV Deficiency. Arterioscler Thromb Vasc Biol. 2019;39(3):373-386. doi:10.1161/ATVBAHA.118.311931

27. Horton JD, Goldstein JL, Brown MS. SREBPs: transcriptional mediators of lipid homeostasis. J Clin Invest. 2002;109(9):1125-1131.doi: 10.1172/JCI15593

28. Okazaki M, Usui S, Ishigami M, et al. Identification of unique lipoprotein subclasses for visceral obesity by component analysis of cholesterol profile in high- performance liquid chromatography. Arterioscler Thromb Vasc Biol. 2005;25(3):578-584. doi:10.1161/01.ATV.0000155017.60171.88

29. Carlson SE, Goldfarb S. A sensitive enzymatic method for determination of free and esterified tissue cholesterol. Clin Chim Acta Int J Clin Chem. 1977;79(3):575-582. doi:10.1016/0009-8981(77)90178-4

30. Brahm AJ, Hegele RA. Chylomicronaemia--current diagnosis and future therapies. Nat Rev Endocrinol. 2015;11(6):352-362. doi:10.1038/nrendo.2015.26

31. Abu-Elheiga L, Matzuk MM, Abo-Hashema KA, Wakil SJ. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science. 2001;291(5513):2613-2616. doi:10.1126/science.1056843

32. Kim C-W, Addy C, Kusunoki J, et al. Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation. Cell Metab. 2017;26(2):394-406.e6. doi:10.1016/j.cmet.2017.07.009

33. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343-1351. doi:10.1172/JCI23621

34. Benassayag C, Mignot TM, Haourigui M, et al. High polyunsaturated fatty acid, thromboxane A2, and alpha-fetoprotein concentrations at the human feto-maternal interface. J Lipid Res. 1997;38(2):276-286.

35. Hirano Y, Murata S, Tanaka K, Shimizu M, Sato R. Sterol regulatory element- binding proteins are negatively regulated through SUMO-1 modification independent of the ubiquitin/26 S proteasome pathway. J Biol Chem. 2003;278(19):16809-16819. doi:10.1074/jbc.M212448200

36. Shimano H, Sato R. SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology. Nat Rev Endocrinol. 2017;13(12):710-730. doi:10.1038/nrendo.2017.91

37. Zimmer M, Bista P, Benson EL, et al. CAT-2003: A novel sterol regulatory element- binding protein inhibitor that reduces steatohepatitis, plasma lipids, and atherosclerosis in apolipoprotein E*3-Leiden mice. Hepatol Commun. 2017;1(4):311-325. doi:10.1002/hep4.1042

38. Lee J, Goldberg IJ. Hypertriglyceridemia-induced pancreatitis created by oral estrogen and in vitro fertilization ovulation induction. J Clin Lipidol. 2008;2(1):63-66. doi:10.1016/j.jacl.2007.11.001

39. Jiang Y, Tian W. The effects of progesterones on blood lipids in hormone replacement therapy. Lipids Health Dis. 2017;16(1):219. doi:10.1186/s12944-017- 0612-5

40. Ramos-Román MA. Prolactin and lactation as modifiers of diabetes risk in gestational diabetes. Horm Metab Res Horm Stoffwechselforschung Horm Metab. 2011;43(9):593-600. doi:10.1055/s-0031-1284353

41. Williams C, Coltart TM. Adipose tissue metabolism in pregnancy: the lipolytic effect of human placental lactogen. Br J Obstet Gynaecol. 1978;85(1):43-46. doi:10.1111/j.1471-0528.1978.tb15824.x

42. de Pretis N, Amodio A, Frulloni L. Hypertriglyceridemic pancreatitis: Epidemiology, pathophysiology and clinical management. United Eur Gastroenterol J. 2018;6(5):649-655. doi:10.1177/2050640618755002

43. Adiels M, Olofsson S-O, Taskinen M-R, Borén J. Overproduction of very low- density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008;28(7):1225-1236. doi:10.1161/ATVBAHA.107.160192

44. Austin MA, Talmud PJ, Farin FM, et al. Association of apolipoprotein A5 variants with LDL particle size and triglyceride in Japanese Americans. Biochim Biophys Acta. 2004;1688(1):1-9. doi:10.1016/j.bbadis.2003.10.003

45. Mar R, Pajukanta P, Allayee H, et al. Association of the APOLIPOPROTEIN A1/C3/A4/A5 gene cluster with triglyceride levels and LDL particle size in familial combined hyperlipidemia. Circ Res. 2004;94(7):993-999. doi:10.1161/01.RES.0000124922.61830.F0

参考文献をもっと見る

全国の大学の
卒論・修論・学位論文

一発検索!

この論文の関連論文を見る