Impaired bile acid handling and aggravated liver injury in mice expressing a hepatocyte-specific RXRα variant lacking the DNA-binding domain
Impaired bile acid handling and aggravated liver injury in mice expressing a hepatocyte-specific RXRα variant lacking the DNA-binding domain
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DOI：
10.1016/j.jhep.2013.09.026
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发表时间：
2014-02-01
影响因子：
25.7
通讯作者：
Karpen, Saul J.
中科院分区：
文献类型：
--
作者：
Kosters, Astrid;Felix, Julio C.;Karpen, Saul J.
背景和目标：视黄酸X受体a（RXRa）是II类核受体（NR）的主要异源二聚化伴侣，并且是许多肝脏过程的基因表达的主要调节剂，包括通过多个伴侣的胆汁酸（BA）稳态。肝RXRa结构域在异源二聚体功能中对BA负荷或胆管胆汁淤积的响应的具体贡献尚未完全表征。野生型（WT）小鼠和表达缺乏DNA结合结构域的肝细胞特异性RXRa的小鼠（hsRxraDex 4），其保留与其配偶体异二聚化的部分能力，被喂食1%胆酸（CA）饮食5天，3，5-二乙氧基羰基-1，结果：与喂食CA的WT小鼠相比，喂食CA的hsRxaDex 4小鼠的血清ALT（6.5倍; p < 0.05）、AST（9.3倍; p = 0.06）和BA（2.8倍; p < 0.05）增加，但在喂食DDC的基因型之间诱导相同。与WT小鼠相比，饲喂CA使hs-RxraDex 4小鼠中的总胆红素水平（4.4倍; p = 0.06）和未结合胆红素水平（2.2倍; p < 0.02）升高，但在饲喂DDC的hs-RxraDex 4小鼠中未升高。在CA喂养的hsRxraDex 4小鼠中观察到坏死和炎症增加，但在DDC喂养的hsRxraDex 4小鼠中未观察到。在CA和DDC喂养的hs-RxraDex 4小鼠中，细胞凋亡标志物DR 5、CK 8、CK 18 RNA增加。切割的半胱天冬酶3、CK 18和p-JNK蛋白在CA喂养的hs-RxraDex 4小鼠中升高，但在DDC喂养的hs-RxraDex 4小鼠中未升高。在CA喂养和DDC喂养的hs-RxraDex 4小鼠中，Ostb和Cyp 2b 10 RNA的诱导受损。令人惊讶的是，DDC喂养的hs-RxraDex 4小鼠表现出衰减的纤维化相比，DDC喂养的WT mice.Conclusions：这两个模型的胆汁淤积确定共同的和损伤的特定作用RXR α异二聚体和功能的相关性完整的RXRa-DBD在肝细胞适应性胆汁淤积反应。(C)2013年欧洲肝脏研究协会。由Elsevier B出版。V.保留所有权利。
Background & Aims: Retinoid X Receptor a (RXRa) is the principal heterodimerization partner of class II Nuclear Receptors (NRs), and a major regulator of gene expression of numerous hepatic processes, including bile acid (BA) homeostasis through multiple partners. Specific contributions of hepatic RXRa domains in heterodimer function in response to either BA load or ductular cholestasis are not fully characterized.Methods: Wild-type (WT) mice and mice expressing a hepatocyte- specific RXRa lacking the DNA-Binding-Domain (hsRxraDex4), which retains partial ability to heterodimerize with its partners, were fed a 1% cholic acid (CA) diet for 5 days, a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 3 weeks, or control diet.Results: Serum ALT (6.5-fold; p < 0.05), AST (9.3-fold; p = 0.06) and BA (2.8-fold; p < 0.05) were increased in CA-fed hsRxaDex4 mice compared to CA-fed WT mice, but were equally induced between genotypes by DDC-feeding. CA-feeding elevated total (4.4-fold; p = 0.06) and unconjugated (2.2-fold; p < 0.02) bilirubin levels in hs-RxraDex4 mice compared to WT mice, but not in DDC-fed hs-RxraDex4 mice. Increased necrosis and inflammation was observed in CA-fed, but not in DDC-fed hsRxraDex4 mice. Apoptotic markers DR5, CK8, CK18 RNA were increased in CA-and DDC-fed hs-RxraDex4 mice. Cleaved caspase 3, CK18 and p-JNK protein were elevated in CA-fed but not in DDC-fed hs-RxraDex4 mice. Induction of Ostb and Cyp2b10 RNA was impaired in CA-fed and DDC-fed hs-RxraDex4 mice. Surprisingly, DDC-fed hs-RxraDex4 mice showed attenuated fibrosis compared to DDC-fed WT mice.Conclusions: These two models of cholestasis identify common and injury-specific roles for RXRa heterodimers and the functional relevance of an intact RXRa-DBD in the hepatocytic adaptive cholestatic response. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.