Beta-Arrestin 1 Mediates Liver Thyrotropin Regulation of Cholesterol Conversion Metabolism via the Akt-Dependent Pathway

الملخص EN

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.