Beta-Arrestin 1 Mediates Liver Thyrotropin Regulation of Cholesterol Conversion Metabolism via the Akt-Dependent Pathway
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...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2018-01-01
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| Series: | International Journal of Endocrinology |
| Online Access: | http://dx.doi.org/10.1155/2018/4371396 |
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| Summary: | 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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| ISSN: | 1687-8337 1687-8345 |