Beta Arrestin 1 Mediates Liver TSH Regulation of Cholesterol Metabolism Via AKT-Dependent Pathway
Presentation Number: SUN 273
Date of Presentation: April 2nd, 2017
Tao Bo*1, Shaona Niu2, Shanshan Shao3, Ling Gao1 and Jiajun Zhao4
1Shandong Provincial Hospital affiliated to Shandong University, Jinan, China, 2Shandong Academy of Clinical Medicine, Jinan, China, 3Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 4Institute of Endocrinology, Shandong Academy of Clinical Medicine., Jinan, China
GPCR was known as the largest superfamily for signal transduction and transmission for years. After activation of specific ligands, GPCRs were subsequently desensitized and internalized by β arrestins. What’s more, it was reported that β arrestins can also initiated a second wave of signal transmission independent of G proteins, in which it performed as multifunctional adaptors in several metabolic pathways. It was clear that GPCRs could regulate virtually all known physiological processes in humans, whereas specific roles for arrestin–mediated G protein–independent signaling pathway were much less reported.
TSHR is one of the GPCR members that mediated the function of TSH by its highly specific interactions. In our previous study, TSHR was identified in liver tissue, and the major role of liver TSHR in cholesterol metabolism was illustrated, as TSH could repress hepatic cholesterol conversion level via a SREBP2/HNF4α/CYP7A1 signaling pathway. However, the particular metabolic significance of liver β arrestins in TSH initiated cholesterol metabolism pathways is not illustrated yet.
In this study, the effects of β arrestin–mediated signaling in TSH regulated cholesterol metabolism were discussed. Compared to wildtype (WT) controls, free cholesterol (FC) and total cholesterol (TC) levels were decreased in β arrestin knockout mice and knockdown HepG2 cells, especially β arrestin 1 (ARRB1): FC (mmol/g protein), 0.212±0.049 in liver of ARRB1-/- mice versus 0.399±0.014 in WT ,P<0.05; 0.037±0.005 in ARRB1 knockdown cells versus 0.048±0.002 in control; TC (mmol/g protein), 0.240±0.070 in liver of ARRB1-/- mice versus 0.490±0.005 in WT, P<0.05; 0.053±0.004 in ARRB1 knockdown cells versus 0.076±0.010 in control, P<0.05. What’s more, CYP7A1, which is the rate-limiting enzyme in bile acid synthesis, was increased due to the deficiencies of β arrestins. The reason might be related to the change of AKT phosphorylation level, which was recognized as downstream effects of β arrestin-related biased pathways. Deficiencies of arrestins led to a decreased level of TSH-stimulated AKT phosphorylation, lower the level of mature SREBP2, which is an important transcription factor that regulates cholesterol conversion. Subsequently, the inhibition effects of SREBP2 towards CYP7A1 were reduced. AKT activator SC79, but not TSH, could up-regulate AKT phosphorylation level in β arrestins knockdown HepG2 cells, and subsequently heightened mature SREBP2 and down-regulated cholesterol level. These results implied that TSH-stimulated AKT phosphorylation was partially rely on β arrestins. Together, our results demonstrated that β arrestins, especially ARRB1, involved in TSH-regulated cholesterol metabolism through AKT pathway. Therefore, arrestins may be the important adaptors that link TSH stimulation to cell second messengers, such as AKT.
Nothing to Disclose: TB, SN, SS, LG, JZ