Nuclear receptor CAR (NR1I3) is essential for DDC-induced liver injury and oval cell proliferation in mouse liver.
Nuclear receptor CAR (NR1I3) is essential for DDC-induced liver injury and oval cell proliferation in mouse liver.
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DOI：
10.1038/labinvest.2011.115
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发表时间：
2011-11
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--
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肝脏具有再生肝细胞以响应损伤的能力。当这种再生能力在肝损伤期间受损时，被认为是出生后肝祖细胞的卵圆细胞增殖并分化成肝细胞。在这里，我们已经证明，3，5-二乙氧羰基-1，4-二氢可力丁（DDC）激活核受体组成型活性/雄烷受体（CAR），导致小鼠肝脏卵圆细胞增殖。在向Car +/+小鼠喂食含0.1% DDC的饲料后，通过肝细胞核CAR蓄积和细胞色素P450（CYP）2B 10 mRNA诱导显示DDC对CAR的激活。在喂食DDC饮食后，Car +/+，而不是Car−/−小鼠，在门静脉周围区域出现严重的肝损伤和A6抗体染色的小管反应。通过激光捕获显微切割和实时PCR证实卵圆细胞增殖;两种卵圆细胞标志物上皮细胞粘附分子和TROP 2的mRNA在DDC饮食喂养的Car +/+小鼠的门静脉周围区域特异性诱导，但不是Car−/−小鼠。虽然肝细胞的生长和死亡率最初仅在DDC饮食喂养的Car +/+小鼠中增强，但当卵圆细胞增殖时，生长减弱，而死亡继续有增无减。DDC诱导的肝损伤与其他CAR激活剂（如苯巴比妥）不同，发生在门静脉周围区域，其中细胞发生肥大，积累卟啉晶体和炎症，所有这些都与卵圆细胞的增殖有关。因此，CAR为进一步研究其在肝再生中的作用以及肝细胞癌等疾病的发展提供了极好的实验模型。
The liver is endowed with the ability to regenerate hepatocytes in response to injury. When this regeneration ability is impaired during liver injury, oval cells, which are considered to be postnatal hepatic progenitors, proliferate and differentiate into hepatocytes. Here we have demonstrated that 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) activates the nuclear receptor constitutive active/androstane receptor (CAR), resulting in proliferation of oval cells in mouse liver. Activation of CAR by DDC was shown by hepatic nuclear CAR accumulation and cytochrome P450 (CYP)2B10 mRNA induction after feeding a 0.1% DDC-containing diet to Car +/+ mice. After being fed the DDC diet, Car +/+, but not Car−/− mice, developed severe liver injury and an A6 antibody-stained ductular reaction in an area around the portal tract. Oval cell proliferation was confirmed by laser capture microdissection and real-time PCR; mRNAs for the two oval cell markers epithelial cell adhesion molecule and TROP2 were specifically induced in the periportal region of DDC diet-fed Car +/+, but not Car−/− mice. Although rates of both hepatocyte growth and death were initially enhanced only in DDC diet-fed Car +/+ mice, growth was attenuated when oval cells proliferated, whereas death continued unabated. DDC-induced liver injury, which differs from other CAR activators such as phenobarbital, occurred in the periportal region where cells developed hypertrophy, accumulated porphyrin crystals and inflammation developed, all in association with the proliferation of oval cells. Thus, CAR provides an excellent experimental model for further investigations into its roles in liver regeneration, as well as the development of diseases such as hepatocellular carcinoma.
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