Retinoid X Receptor Alpha Regulates The Mechanism Of Hepatitis B Virus Infection

Hepatitis B virus(HBV)infection remains a major public health problem globally with more than 240 million people chronically infected worldwide,who are at high risk of progression to cirrhosis,liver failure or hepatocarcinoma.Sodium taurocholate cotransporting polypeptide(NTCP),a primary hepatic bile acid transporter,was recently identified as a functional receptor for HBV and its satellite virus Hepatitis D virus(HDV).NTCP is predominantly expressed in liver and its expression is precisely regulated by a complex network comprised by various transcription factors,such as the retinoid X receptor alpha(RXRa)and farnesoid X receptor(FXR),which are both liver-enriched nuclear receptors and play an important role in bile acid metabolism.Among nuclear receptors,RXRa is unique in that it serves as an obligatory common heterodimerization partner for other type ? nuclear receptors,e.g.the retinoic acid receptor and FXR.Mice lacking RXRca are embryonically lethal,and RXR? is the most abundant subtype in three RXRs in the adult liver,suggesting that it might have a prominent role in hepatic functions.We found that in both primary Tupaia hepatocytes(PTH)and human NTCP(hNTCP)transfected HepG2 cells,knocking down RXRa by siRNA significantly enhanced HBV infection in these cells,while an agonist of RXR,Bexarotene inhibited HBV early infection in a dose-dependent manner.RXRa silencing or activation by Bexarotene after HBV inoculation had little effect on viral infection.Among these liver-enriched partner proteins of RXR?,only Liver X receptor alpha(LXRa)can negatively regulate HBV early infection,consistent with RXRa,suggesting that RXRa may negatively regulate HBV infection through its interaction with LXR?.Further analysis showed treatment of Bexarotene inhibited[3H]-taurocholate uptake in hNTCP complemented HepG2 cells while silencing RXRa enhanced[3H]-taurocholate uptake.Silencing of RXRa increased NTCP protein expression in hNTCP complemented HepG2 cellsRXR? is a master regulator of hepatic lipid metabolism.RNA-seq analysis revealed that arachidonic acid(AA)metabolism pathways were down-regulated when RXRa was depleted.Prostaglandins are lipid mediators generated from AA and involved in regulating the outcome of many infectious diseases.We found that inhibition of PTGES and PTGDS,two key enzymes in prostaglandin biosynthesis pathways,enhanced HBV early infection.These studies provide new insights into mechanisms that regulate HBV infection;they also indicated that modulating RXRa activity may be useful for the treatment of HBV infection.