Beta-Arrestin 1 Mediates Liver Thyrotropin Regulation of Cholesterol Conversion Metabolism via the Akt-Dependent Pathway.
Beta-Arrestin 1 Mediates Liver Thyrotropin Regulation of Cholesterol Conversion Metabolism via the Akt-Dependent Pathway.
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Beta-Arrestin 1 通过 Akt 依赖性途径介导肝脏促甲状腺素对胆固醇转化代谢的调节
DOI：
10.1155/2018/4371396
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发表时间：
2018
影响因子：
2.8
通讯作者：
Bo T
中科院分区：
文献类型：
--
作者：
Niu S;Li H;Chen W;Zhao J;Gao L;Bo T
G蛋白偶联受体(GPCRs)激活后，被β-arrestins(ARRb)脱敏。此外，ARRBs可以启动不依赖G蛋白的第二波信号传导。促甲状腺激素受体(TSHR)是GPCR成员之一。在我们以前的研究中，TSHR在肝脏中被发现；TSHR在胆固醇代谢中的主要作用被阐明，因为TSH通过cAMP/PKA/CREB/HMGCR和SREBP2/HNF4α/CYP7A1途径来调节肝脏的胆固醇代谢。有报道称，在TSHR内化过程中，ARRB2比ARRB1占优势。然而，ARRBs在促甲状腺激素启动的胆固醇代谢中的意义尚未阐明。在我们的研究中，ARRBs对TSH调节的胆固醇代谢的影响进行了研究。在C57BL/6小鼠和HepG2细胞系中，ARRB1/2基因失活。测量了arrestin基因敲除小鼠和arrestin基因敲除细胞中的胆固醇水平。分析了参与胆固醇代谢的分子。结果表明，ARRB1基因的缺失导致胆固醇水平降低，并降低了TSH刺激的AKT磷酸化。随后，由于成熟SREBP2水平降低，SREBP2对细胞色素P7A1的抑制作用减弱。除ARRB基因敲除细胞中TSH失活外，AKT激活剂SC79还能促进AKT磷酸化和成熟SREBP2水平。我们的结果表明，ARRBs，特别是ARRB1，通过AKT途径参与TSH调节的胆固醇代谢。
After activation, G protein-coupled receptors (GPCRs) are desensitized by β-arrestins (ARRBs). Moreover, ARRBs can initiate a second wave of signaling independent of G proteins. Thyroid-stimulating hormone receptor (TSHR) is one of the GPCR members. In our previous study, TSHR was identified in the liver; the major role of TSHR in cholesterol metabolism was illustrated, as TSH could regulate hepatic cholesterol metabolism via cAMP/PKA/CREB/HMGCR and SREBP2/HNF4α/CYP7A1 pathways. It has been reported that ARRB2 predominates over ARRB1 in TSHR internalization. However, the significance of ARRBs in TSH-initiated cholesterol metabolism has not been illustrated. In our study, the effects of ARRBs on TSH-regulated cholesterol metabolism are investigated. ARRB1/2 was genetically inactivated in C57BL/6 mice and HepG2 cell line, respectively. Cholesterol levels in arrestin-knockout mice and arrestin-knockdown cells were measured. Molecules participating in cholesterol metabolism were analyzed. It turned out that deficiencies in ARRB1 led to decreased cholesterol levels and decreased TSH-stimulated AKT phosphorylation. Subsequently, the inhibitory effect on CYP7A1 by SREBP2 was reduced due to lowered mature SREBP2 level. Other than the failures of TSH in ARRB-knockdown cells, the AKT activator SC79 could enhance AKT phosphorylation and mature SREBP2 level. Our results demonstrate that ARRBs, especially ARRB1, are involved in TSH-regulated cholesterol metabolism through the AKT pathway.
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影响因子：
7.5
作者：
Balzan, Silvana;Nicolini, Giuseppina;Iervasi, Giorgio
通讯作者：
Iervasi, Giorgio
影响因子：
4.8
作者：
Ma, Xiaojie;Espana-Serrano, Laura;Daaka, Yehia
通讯作者：
Daaka, Yehia
影响因子：
4.8
作者：
Oakley, RH;Laporte, SA;Barak, LS
通讯作者：
Barak, LS
影响因子：
5.4
作者：
MENGISTU, M;LUKES, YG;BURMAN, KD
通讯作者：
BURMAN, KD
影响因子：
56.9
作者：
LOHSE, MJ;BENOVIC, JL;LEFKOWITZ, RJ
通讯作者：
LEFKOWITZ, RJ