Abstract
ABSTRACT Hepatocyte proliferation could result in the loss of covalently closed circular DNA (cccDNA) and the emergence of cccDNA-cleared nascent hepatocytes, which appear refractory to hepatitis B virus (HBV) reinfection with unknown mechanism(s). Sodium taurocholate cotransporting polypeptide (NTCP) is the functional receptor for HBV entry. In this study, down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes was found to prevent HBV infection in HepG2-NTCP-tet cells and in liver-humanized mice. In patients, lower NTCP protein expression was correlated well with higher levels of hepatocyte proliferation and less HBsAg expression in HBV-related focal nodular hyperplasia (FNH) tissues. Clinically, significantly lower NTCP protein expression was correlated with more active hepatocyte proliferation in CHB patients with severe active necroinflammation and better antiviral treatment outcome. Mechanistically, the activation of cell cycle regulatory genes p53, S-phase kinase-associated protein 2 (SKP2) and cyclin D1 during cell proliferation, as well as proliferative and inflammatory cytokine Interleukin-6 (IL-6) could transcriptionally down-regulate NTCP expression. From these aspects, we conclude that within the milieu of hepatocyte proliferation, down-regulation of cell membrane localized NTCP expression level renders nascent hepatocytes resistant to HBV reinfection. This may accelerate virus clearance during immune-mediated cell death and compensatory proliferation of survival hepatocytes.
Highlights
Hepatitis B virus (HBV) infection is the major cause of chronic hepatitis B (CHB), cirrhosis, and hepatocellular carcinoma (HCC) worldwide
To explore whether NTCP is down-regulated during hepatocyte proliferation, HepG2-NTCP-tet cells were routinely cultured in Dulbecco’s modified Eagle’s medium (DMEM) and treated with 4 μg/ mL DOX for 4 days and all along afterwards to induce and maintain stable NTCP expression
Compared to those cultured in DMEM, a relative higher expression of NTCP protein in cells cultured in hepatocyte culture medium (HCM) medium was observed, which was in concordant with the result demonstrated by immunofluorescent staining in HepG2-NTCP-tet cells (Figure 1(C))
Summary
Hepatitis B virus (HBV) infection is the major cause of chronic hepatitis B (CHB), cirrhosis, and hepatocellular carcinoma (HCC) worldwide. Since it has been demonstrated that HBV infection can spread to the entire hepatocyte population in the acute phase and in the tolerant phase of chronically infected individuals, it is reasonable to postulate that the uninfected hepatocytes present in the recovered liver should be derived from previously infected hepatocytes [4,5]. How these cells clear the virus remains elusive
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