• 1.南京醫(yī)科大學(xué)附屬南京第一醫(yī)院普外科(南京210006);;
  • 2.上海交通大學(xué)醫(yī)學(xué)院附屬瑞金醫(yī)院外科，上海消化外科研究所（上海200025）;

目的 　研究膽囊膽固醇結(jié)石患者肝臟的核受體基因： 肝臟X受體α (liver X receptor α，LXRα)、法尼醇受體(farnesoid X receptor,FXR)、人類(lèi)固醇異生物受體(steroid xenobiotic receptor,SXR)及肝受體同類(lèi)物1(liver receptor homolog 1，LRH-1)的表達(dá)，探討膽固醇結(jié)石病的發(fā)病機(jī)理。
方法 　27例膽囊膽固醇結(jié)石患者(膽石組)，男6例，女21例，平均年齡(52.44±1.92)歲。10例無(wú)膽石癥的膽囊息肉患者為對(duì)照(對(duì)照組)，男6例，女4例，平均年齡(47.10±2.73)歲。測(cè)定膽石膽固醇成分及血清脂類(lèi)成分： 總膽固醇(TC)、甘油三酯(TG)、高密度脂蛋白膽固醇(HDL-ch)、載脂蛋白(Apo)B和ApoA1和膽汁脂類(lèi)成分(膽固醇、磷脂和膽汁酸)，并計(jì)算膽汁總脂和膽汁膽固醇飽和指數(shù)。實(shí)時(shí)定量PCR法測(cè)定肝臟LRH-1、FXR、SXR及LXRα基因的表達(dá)量。
結(jié)果 　膽石組血清中HDL-ch濃度明顯低于對(duì)照組〔(0.93±0.05) mmol/L vs (1.33±0.09) mmol/L〕, P＜0.001; ApoA1濃度也低于對(duì)照組〔(1.19±0.05) g/L vs (1.36±0.06) g/L〕, P＜0.05; 血清ApoB、TC和TG 2組比較差異均無(wú)統(tǒng)計(jì)學(xué)意義(P gt;0.05)。膽石組膽汁呈膽固醇過(guò)飽和(膽固醇過(guò)飽和指數(shù)： 1.17±0.02 vs 0.79±0.10, P＜0.001)； 膽汁膽固醇摩爾百分比濃度較對(duì)照組升高〔(7.96±0.39) mol〖WTB4〗%〖WTBZ〗 vs (5.26±0.89) mol%〕，P＜0.01； 膽汁總脂較對(duì)照組明顯下降〔(104.72±10.51) g/L vs (154.24±14.20) g/L〕, P＜0.05； 膽汁中膽汁酸和磷脂成分2組比較差異均無(wú)統(tǒng)計(jì)學(xué)意義(P gt;0.05)。膽石組LRH-1表達(dá)高于對(duì)照組(14.18±1.80 vs 7.22±2.22)，P＜0.05，LXRα、FXR和SXR表達(dá)2組差異無(wú)統(tǒng)計(jì)學(xué)意義(P gt;0.05)。
結(jié)論 　人類(lèi)肝臟LRH-1的表達(dá)增高與膽囊膽固醇結(jié)石形成有關(guān)。

引用本文： 楊士勇,王建承,韓天權(quán),王小平,蔡劬,姜志宏,蔣兆彥,蔡杏興,張圣道. 膽固醇結(jié)石患者肝臟核受體基因表達(dá)的研究. 中國(guó)普外基礎(chǔ)與臨床雜志, 2008, 15(10): 751-755. doi: 復(fù)制

1. 　McKenna NJ, O’Malley BW. Combinatorial control of gene expression by nuclear receptors and coregulators [Ｊ]. Cell, 2002; 108(4)∶465.
2. 　Lammert F, Carey MC, Paigen B. Chromosomal organization of candidate genes involved in cholesterol gallstone formation： a murine gallstone map [Ｊ]. Gastroenterology, 2001; 120(1)∶221.
3. 　Fayard E, Auwerx J, Schoonjans K. LRH-1: an orphan nuclear receptor involved in development, metabolism and steroidogenesis [Ｊ]. Trends Cell Biol, 2004; 14(5)∶250.
4. 　Eloranta JJ, Kullak-Ublick GA. Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism [Ｊ]. Arch Biochem Biophys, 2005; 433(2)∶397.
5. 　Liu Y, Binz J, Numerick MJ, et al. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis [Ｊ]. J Clin Invest, 2003; 112(11)∶16786　Wang DQ, Afdhal NH. Genetic analysis of cholesterol gallstone formation： searching for Lith (gallstone) genes [Ｊ]. Curr Gastroenterol Rep, 2004; 6(2)∶140.
6. 　孔凡民， 隋春陽(yáng)， 李航宇， 等. 膽囊膽固醇結(jié)石與肝細(xì)胞膽管膜上轉(zhuǎn)運(yùn)子BSEP、MRP2和MDR3關(guān)系的研究 [Ｊ]. 中國(guó)普外基礎(chǔ)與臨床雜志, 2006; 13(3)∶314.
7. 　劉君， 龍厚勇， 明晗昕， 等. 肝細(xì)胞MDR1基因表達(dá)與膽囊膽固醇結(jié)石相關(guān)性研究 [Ｊ]. 中國(guó)普外基礎(chǔ)與臨床雜志, 2005; 12(4)∶346.
8. 　湯文浩, 韓天權(quán), 張圣道. 測(cè)定膽汁膽固醇和磷脂的簡(jiǎn)捷方法 [Ｊ]. 上海醫(yī)學(xué)檢驗(yàn)雜志, 1994; 9(2)∶122.
9. 　Carey MC. Critical tables for calculating the cholesterol saturation of native bile [Ｊ]. J Lipid Res, 1978; 19(8)∶945.
10. 　傅培彬， 張圣道， 戴坤揚(yáng)， 等. 以膽石剖面結(jié)構(gòu)及化學(xué)成分為基礎(chǔ)的膽石分類(lèi)法 [Ｊ]. 中華外科雜志, 1984, 22(4)∶258.
11. 　Escriva H, Delaunay F, Laudet V. Ligand binding and nuclear receptor evolution [Ｊ]. Bioessays, 2000; 22(8)∶717.
12. 　Moschetta A, Bookout AL, Mangelsdorf DJ. Prevention of cholesterol gallstone disease by FXR agonists in a mouse model [Ｊ]. Nat Med, 2004; 10(12)∶1352.
13. 　Kosters A, Jirsa M, Groen AK. Genetic background of cholesterol gallstone disease [Ｊ]. Biochim Biophys Acta, 2003; 1637(1)∶1.
14. 　Moschetta A, vanBerge-Henegouwen GP, Portincasa P, et al. Cholesterol crystallization in model biles： effects of bile salt and phospholipid species composition [Ｊ]. J Lipid Res, 2001; 42(8)∶1273.
15. 　蔣兆彥， 韓天權(quán)， 所廣軍， 等. 膽固醇結(jié)石病人肝臟膽小管側(cè)膜ATP基因表達(dá)差異的研究 [Ｊ]. 外科理論與實(shí)踐, 2005; 10(1)∶61.
16. 　Bertolotti M, Gabbi C, Anzivino C, et al. Decreased hepatic expression of PPAR-gamma coactivator-1 in cholesterol cholelithiasis [Ｊ]. Eur J Clin Invest, 2006; 36(3)∶170.
17. 　Staudinger JL, Goodwin B, Jones SA, et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity [Ｊ]. Proc Natl Acad Sci USA, 2001; 98(6)∶3369.
18. 　Schoonjans K, Annicotte JS, Huby T, et al. Liver receptor homolog 1 controls the expression of the scavenger receptor class B type Ⅰ [Ｊ]. EMBO Rep, 2002; 3(12)∶1181.
19. 　Freeman LA, Kennedy A, Wu J, et al. The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter [Ｊ]. J Lipid Res, 2004; 45(7)∶1197.
20. 　Luo Y, Liang CP, Tall AR. The orphan nuclear receptor LRH-1 potentiates the sterol-mediated induction of the human CETP gene by liver X receptor [Ｊ]. J Biol Chem, 2001; 276(27)∶24767.
  1. 1. 　McKenna NJ, O’Malley BW. Combinatorial control of gene expression by nuclear receptors and coregulators [Ｊ]. Cell, 2002; 108(4)∶465.
  2. 2. 　Lammert F, Carey MC, Paigen B. Chromosomal organization of candidate genes involved in cholesterol gallstone formation： a murine gallstone map [Ｊ]. Gastroenterology, 2001; 120(1)∶221.
  3. 3. 　Fayard E, Auwerx J, Schoonjans K. LRH-1: an orphan nuclear receptor involved in development, metabolism and steroidogenesis [Ｊ]. Trends Cell Biol, 2004; 14(5)∶250.
  4. 4. 　Eloranta JJ, Kullak-Ublick GA. Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism [Ｊ]. Arch Biochem Biophys, 2005; 433(2)∶397.
  5. 5. 　Liu Y, Binz J, Numerick MJ, et al. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis [Ｊ]. J Clin Invest, 2003; 112(11)∶16786　Wang DQ, Afdhal NH. Genetic analysis of cholesterol gallstone formation： searching for Lith (gallstone) genes [Ｊ]. Curr Gastroenterol Rep, 2004; 6(2)∶140.
  6. 6. 　孔凡民， 隋春陽(yáng)， 李航宇， 等. 膽囊膽固醇結(jié)石與肝細(xì)胞膽管膜上轉(zhuǎn)運(yùn)子BSEP、MRP2和MDR3關(guān)系的研究 [Ｊ]. 中國(guó)普外基礎(chǔ)與臨床雜志, 2006; 13(3)∶314.
  7. 7. 　劉君， 龍厚勇， 明晗昕， 等. 肝細(xì)胞MDR1基因表達(dá)與膽囊膽固醇結(jié)石相關(guān)性研究 [Ｊ]. 中國(guó)普外基礎(chǔ)與臨床雜志, 2005; 12(4)∶346.
  8. 8. 　湯文浩, 韓天權(quán), 張圣道. 測(cè)定膽汁膽固醇和磷脂的簡(jiǎn)捷方法 [Ｊ]. 上海醫(yī)學(xué)檢驗(yàn)雜志, 1994; 9(2)∶122.
  9. 9. 　Carey MC. Critical tables for calculating the cholesterol saturation of native bile [Ｊ]. J Lipid Res, 1978; 19(8)∶945.
  10. 10. 　傅培彬， 張圣道， 戴坤揚(yáng)， 等. 以膽石剖面結(jié)構(gòu)及化學(xué)成分為基礎(chǔ)的膽石分類(lèi)法 [Ｊ]. 中華外科雜志, 1984, 22(4)∶258.
  11. 11. 　Escriva H, Delaunay F, Laudet V. Ligand binding and nuclear receptor evolution [Ｊ]. Bioessays, 2000; 22(8)∶717.
  12. 12. 　Moschetta A, Bookout AL, Mangelsdorf DJ. Prevention of cholesterol gallstone disease by FXR agonists in a mouse model [Ｊ]. Nat Med, 2004; 10(12)∶1352.
  13. 13. 　Kosters A, Jirsa M, Groen AK. Genetic background of cholesterol gallstone disease [Ｊ]. Biochim Biophys Acta, 2003; 1637(1)∶1.
  14. 14. 　Moschetta A, vanBerge-Henegouwen GP, Portincasa P, et al. Cholesterol crystallization in model biles： effects of bile salt and phospholipid species composition [Ｊ]. J Lipid Res, 2001; 42(8)∶1273.
  15. 15. 　蔣兆彥， 韓天權(quán)， 所廣軍， 等. 膽固醇結(jié)石病人肝臟膽小管側(cè)膜ATP基因表達(dá)差異的研究 [Ｊ]. 外科理論與實(shí)踐, 2005; 10(1)∶61.
  16. 16. 　Bertolotti M, Gabbi C, Anzivino C, et al. Decreased hepatic expression of PPAR-gamma coactivator-1 in cholesterol cholelithiasis [Ｊ]. Eur J Clin Invest, 2006; 36(3)∶170.
  17. 17. 　Staudinger JL, Goodwin B, Jones SA, et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity [Ｊ]. Proc Natl Acad Sci USA, 2001; 98(6)∶3369.
  18. 18. 　Schoonjans K, Annicotte JS, Huby T, et al. Liver receptor homolog 1 controls the expression of the scavenger receptor class B type Ⅰ [Ｊ]. EMBO Rep, 2002; 3(12)∶1181.
  19. 19. 　Freeman LA, Kennedy A, Wu J, et al. The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter [Ｊ]. J Lipid Res, 2004; 45(7)∶1197.
  20. 20. 　Luo Y, Liang CP, Tall AR. The orphan nuclear receptor LRH-1 potentiates the sterol-mediated induction of the human CETP gene by liver X receptor [Ｊ]. J Biol Chem, 2001; 276(27)∶24767.