SLC22A1 resists HBV by activating JAK/STAT pathway and predicts effect of pegIFNα-based therapy on CHB

Abstract

Background Functional cure is the ideal treatment endpoint of chronic hepatitis B (CHB). Currently, only a few patients achieve this with treatment. Host differences must be influential. Solute Carrier Family 22 Member 1 (SLC22A1), encoding organic cation transporter 1, is expressed in the liver and mediates substance transport of hepatocytes. The association between SLC22A1 and CHB has not been determined. Our objective was to elucidate this association. Methods RNA-seq was performed to explore the changes caused by HBV and SLC22A1. SLC22A1 of plasma and liver biopsies in healthy controls and CHB were measured by ELISA and immunohistochemistry. Plasma from 200 patients with CHB (120 uncured, 80 cured) completing the pegIFNα-based treatment was collected at baseline, 12 and 24 weeks of treatment and measured with ELISA. Results SLC22A1 was downregulated by HBV, as indicated by comparing SLC22A1 of hepG2 and HBV-expression hepG2 cells (hepG2 transfected with pHBV1.3, hepG2.2.15 or hepG2-NTCP infected by HBV) and of both liver and plasma in CHB and healthy volunteers. Plasma SLC22A1 in cured group rose dynamically but not in uncured group. Plasma SLC22A1 at 24 weeks was predictive of functional cure (AUC=0.887) and better when combined with HBsAg at 24 weeks (AUC=0.925). Vitro experiments regarding overexpression of SLC22A1 in hepG2.2.15 demonstrated that HBsAg and HBeAg were inhibited by SLC22A1 through JAK/STAT pathway activation, consistent with transcriptome sequencing results. Conclusions HBV inhibits SLC22A1 expression and SLC22Al suppresses HBV by activating the JAK/STAT pathway. SLC22A1 is a predictor of the functional cure of CHB with pegIFNα-based treatment.