Peroxisome proliferator-activated receptor α (PPARα)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice
Peroxisome proliferator-activated receptor α (PPARα)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice
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DOI：
10.1042/bj20020981
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发表时间：
2003-02-01
影响因子：
4.1
通讯作者：
Kuipers, F
中科院分区：
文献类型：
--
作者：
Kok, T;Bloks, VW;Kuipers, F
过氧化物酶体增殖物激活受体α(PPARpha)是一种核受体，控制与脂质代谢有关的基因的表达，并被脂肪酸和降血脂的贝特类激活。贝特类药物诱导小鼠多药耐药2(MDR2)在肝脏中的表达，MDR2编码小管磷脂转运体。PPARpha在调节mdr2和其他参与胆汁形成的基因中的生理作用尚不清楚。我们发现，肝脏中的ATP结合盒转运蛋白基因mdr2、bsep(胆盐输出泵)、mdr1a/1b、ABCA1和Abcg5/Abcg8(与胆固醇转运有关)、胆盐摄取系统Ntcp(Na+-牛磺胆酸盐共转运多肽基因)和Oatp1(有机阴离子转运多肽I基因)在野生型和PPARpha(-/-)小鼠的胆汁形成中的表达没有差异。环丙贝特(0.05%，w/w，连续2周)可明显诱导野生型小鼠mdr2(+3倍)、mdr1a(+6倍)和mdr1b(+11倍)mRNAs的表达，而Oatp1(-5倍)的mRNAs表达明显降低。MDR2蛋白水平升高，而BSEP、Ntcp和Oatp1蛋白水平显著下降。培养的野生型小鼠肝细胞暴露于PPARpha激动剂后，可特异性地诱导MDR2的mRNA水平，但不影响MDR1a/1b的表达。在贝特治疗的野生型小鼠中，转运蛋白表达的改变与胆汁流量增加约400%有关：磷脂和胆固醇的分泌只有在高胆盐输注期间才增加。在PPARpha((-/-))小鼠中没有观察到贝特效应。综上所述，我们的结果表明，PPARα缺乏对小鼠的基础胆汁形成没有影响。贝特类药物诱导MDR2mRNA和MDR2蛋白水平是由PPARpha介导的，而体内MDR1a/1b的诱导可能反映了与慢性PPARpha激活有关的继发性现象。
Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor that controls expression of genes involved in lipid metabolism and is activated by fatty acids and hypolipidaemic fibrates. Fibrates induce the hepatic expression of murine multidrug resistance 2 (Mdr2), encoding the canalicular phospholipid translocator. The physiological role of PPARalpha in regulation of Mdr2 and other genes involved in bile formation is unknown. We found no differences in hepatic expression of the ATP binding cassette transporter genes Mdr2, Bsep (bile salt export pump), Mdr1a/1b, Abca1 and Abcg5/Abcg8 (implicated in cholesterol transport), the bile salt-uptake systems Ntcp (Na+-taurocholate co-transporting polypeptide gene) and Oatp1 (organic anion-transporting polypeptide I gene) or in bile formation between wild-type and Pparalpha((-/-)) mice. Upon treatment of wild-type mice with ciprofibrate (0.05 %, w/w, in diet for 2 weeks), the expression of Mdr2 (+ 3-fold), Mdr1a (+ 6-fold) and Mdr1b (+ 11-fold) mRNAs was clearly induced, while that of Oatp1 (- 5-fold) was reduced. Mdr2 protein levels were increased, whereas Bsep, Ntcp and Oatp1 were drastically decreased. Exposure of cultured wildtype mouse hepatocytes to PPARalpha agonists specifically induced Mdr2 mRNA levels and did not affect expression of Mdr1a/1b. Altered transporter expression in fibrate-treated wild-type mice was associated with a approximate to 400 % increase in bile flow: secretion of phospholipids and cholesterol was increased only during high-bile-salt infusions. No fibrate effects were observed in Pparalpha((-/-)) mice. In conclusion, our results show that basal bile formation is not affected by PPARalpha deficiency in mice. The induction of Mdr2 mRNA and Mdr2 protein levels by fibrates is mediated by PPARalpha, while the induction of Mdr1a/1b in vivo probably reflects a secondary phenomenon related to chronic PPARalpha activation.