Dietary cholesterol stimulates CYP7A1 in rats because farnesoid X receptor is not activated.
Dietary cholesterol stimulates CYP7A1 in rats because farnesoid X receptor is not activated.
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DOI：
10.1152/ajpgi.00397.2003
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发表时间：
2004-05
期刊：
影响因子：
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通讯作者：
Guorong Xu;Lu-xing Pan;Hai Li;Q. Shang;A. Honda;S. Shefer;J. Bollineni;Y. Matsuzaki;G. Tint;G. Salen
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文献类型：
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作者：
Guorong Xu;Lu-xing Pan;Hai Li;Q. Shang;A. Honda;S. Shefer;J. Bollineni;Y. Matsuzaki;G. Tint;G. Salen
高脂饮食可上调大鼠的细胞色素P7A1，下调兔的细胞色素P7A1的表达。为阐明胆固醇喂养大鼠肝细胞色素P7A1(CyP7A1)表达上调的机制，观察了膳食胆固醇(CH)和胆酸(CA)对肝脏X受体(LXR-α)和类氟砷X受体(FXR)这两种正性和负性调节细胞色素P7A1的核受体激活的影响。雄性SD大鼠分为4组(n=12只/组)，分别饲喂普通饲料(对照组)、2%CH、2%CH+1%CA和1%CA，共1wk。FXR靶基因短二聚体(SHP)和胆盐输出泵(BSEP)的mRNA表达变化反映FXR的激活，而LXR-α的靶基因ABCA1和脂蛋白脂酶(LPL)的表达反映FXR的激活。在胆酸池大小不变的情况下，单独饲喂CH的大鼠，其胆汁酸池大小分别增加了一倍和70%，而添加CA后分别下降了43%和49%，胆汁酸池扩大了3.4倍。灌胃CH后SHP和BSEP基因表达水平无明显变化，但CH+CA组SHP和BSEP基因表达水平分别增加88%和37%。这表明FXR被扩张的胆酸池激活。当饲喂CH或CH+CA时，肝脏氧固醇组和LXR-α的配体浓度增加，以激活LXR-α，ABCA1和LPL的mRNA水平增加证明了这一点。单独饲喂CA后，胆汁酸池增大3倍，SHP和BSEP的表达均增加。这些结果表明，在同时饲喂CH或CH+CA的大鼠中，LXR-α被激活，而只有在胆汁酸库没有扩大到FXR不被激活的情况下，才能诱导CYP7A1的mRNA和活性。在喂饲CH+CA的大鼠中，胆酸池扩大，从而激活FXR以抵消LXR-α对细胞色素P7A1的刺激作用。
Cholesterol feeding upregulates CYP7A1 in rats but downregulates CYP7A1 in rabbits. To clarify the mechanism responsible for the upregulation of CYP7A1 in cholesterol-fed rats, the effects of dietary cholesterol (Ch) and cholic acid (CA) on the activation of the nuclear receptors, liver X-receptor (LXR-alpha) and farsenoid X-receptor (FXR), which positively and negatively regulate CYP7A1, were investigated in rats. Studies were carried out in four groups (n = 12/group) of male Sprague-Dawley rats fed regular chow (control), 2% Ch, 2% Ch + 1% CA, and 1% CA alone for 1 wk. Changes in mRNA expression of short heterodimer partner (SHP) and bile salt export pump (BSEP), target genes for FXR, were determined to indicate FXR activation, whereas the expression of ABCA1 and lipoprotein lipase (LPL), target genes for LXR-alpha, reflected activation. CYP7A1 mRNA and activity increased twofold and 70%, respectively, in rats fed Ch alone when the bile acid pool size was stable but decreased 43 and 49%, respectively, after CA was added to the Ch diet, which expanded the bile acid pool 3.4-fold. SHP and BSEP mRNA levels did not change after feeding Ch but increased 88 and 37% in rats fed Ch + CA. This indicated that FXR was activated by the expanded bile acid pool. When Ch or Ch + CA were fed, hepatic concentrations of oxysterols, ligands for LXR-alpha increased to activate LXR-alpha, as evidenced by increased mRNA levels of ABCA1 and LPL. Feeding CA alone enlarged the bile acid pool threefold and increased the expression of both SHP and BSEP. These results suggest that LXR-alpha was activated in rats fed both Ch or Ch + CA, whereas CYP7A1 mRNA and activity were induced only in Ch-fed rats where the bile acid pool was not enlarged such that FXR was not activated. In rats fed Ch + CA, the bile acid pool expanded, which activated FXR to offset the stimulatory effects of LXR-alpha on CYP7A1.