Transthyretin Regulated by linc00657/miR-205-5p Promoted Cholesterol Metabolism by Inducing SREBP2-HMGCR and Inhibiting LXRα-CYP7A1

Background: Transthyretin functions as a serum transport protein for retinol. Transthyretin has been found associated with amyloid diseases and it is an important nutrition indicator. For this study, we aimed to investigate the up and down stream molecular mechanisms of Transthyretin in cholesterol metabolism.

Methods: We have recruited 237 fatty liver patients to evaluate the serum Transthyretin and its association with cholesterol and other clinical characteristics. And then Transthyretin was up and down regulated by plasmids to investigate its downstream mechanisms in vitro.

Results: Linc00657 (NORAD) and miR-205-5p were further confirmed as upstream mechanisms to regulate Transthyretin. High level Transthyretin patients tended to have higher cholesterol, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) level than low level Transthyretin patients. Moreover, Transthyretin expressed higher in LO2 than that in QSG7701. Furthermore, Transthyretin negatively regulated CYP7A1, LXRα and ABCG 5/8 and positively regulated HMGCR and SREBP2. Linc00657 expressed lower in LO2 than that in QSG7701 and miR-205-5p expressed higher in LO2 than that in QSG7701. Furthermore, we found that linc00657 negatively regulated miR-205-5p and Transthyretin in vitro. And, up regulation of miR-205-5p in linc00657-LO2 cell line could reverse the inhibitory effects of linc00657 on Transthyretin.

Conclusion: Transthyretin regulated cholesterol metabolism mainly through inhibiting LXRα-CYP7A1 and promoting SREBP2-HMGCR. And linc00657 could negatively regulate Transthyretin by inhibiting miR-205-5p, providing novel therapeutic targets for decreasing serum cholesterol level. Besides, Transthyretin could be a potential novel biomarker for predicting liver function along with AST and ALT.