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phase arrest. [235] Another study, however, in Huh7 cells and to demonstrate overall modest HBV-mediated changes
primary marmoset hepatocytes, demonstrated an HBV- in lipid metabolism, but specific factors involved in both
mediated stall in the G2 phase of the cell cycle. [236] While cholesterol and bile acid metabolism were significantly
somewhat contradictory, these results together correlate altered. Interestingly, similar results were seen in a
well with the results of other studies showing that HBV comparison of HBV-infected humanized mice, mice
replication is increased when the cell cycle is arrested in treated with the HBV entry inhibitor Myrcludex-B, which
either G or G , but HBV replication is decreased during mimics the preS1 domain and binds to hNTCP to block
2
1
S phase, when cellular DNA synthesis would be higher, HBV infection, and liver biopsy samples from chronically
potentially depleting the pool of nucleotides that would HBV-infected individuals. [180] Together these results
be available for HBV replication. [237,238] indicate that the binding of HBV to hNTCP inhibits bile acid
uptake, which stimulates bile acid synthesis pathways.
Much of the HBV-mediated regulation of the cell One interesting caveat to these studies is the relatively
cycle appears to be through the activity of the HBx novel use of a direct infection system, which drastically
protein. Multiple studies in primary hepatocytes have alters the question being asked in the experiment. For
demonstrated that HBx alters cell cycle regulators, example, by also using the preS1 mimic Myrcludex-B, the
including decreasing p15 and p16 expression, studies are specifically addressing the impact of receptor
decreasing DNA synthesis, and increasing p21, p27, binding by HBV, and not the cellular impact of HBV
cyclin D1, and cyclin E expression. [85,185,239] Together replication. This is in contrast to some previous work,
these results suggest that HBx drives hepatocytes into which has typically been done using systems that bypass
the cell cycle but increases expression of inhibitors the infection step. An example of the importance of this
that prevent progression beyond G . This HBx- distinction is that while the study using HBV-infected
1
mediated regulation of the cell cycle could have a human-liver chimeric mice demonstrated that by binding
long-term impact on hepatocyte physiology, altering to hNTCP, HBV alters the levels of nuclear farnesoid X
hepatocyte proliferation pathways and contributing to receptor (FXR) and small heterodimer partner (SHP),
the development of HBV-associated disease and HCC. previous work in an HBV-tg mouse model (which bypasses
the infection step, among other differences) showed that
HBV and metabolism depletion of FXR and SHP signaling did not diminish
Because of the primary role of the liver as a metabolic viral replication or transcription. [243] This suggests that
organ, a growing body of research has begun to investigate although HBV binding to its receptor alters the expression
the impact of HBV infection on metabolic pathways in of these transcription factors, this alteration might not
HBV-infected cells. In fact, HBV has been referred to as affect HBV replication. Further research would be needed
a “metabolovirus” due to the perceived intersection to determine the relevance of similar contrasting results
between HBV gene expression and control of cellular within different model systems.
metabolism. [206,240] Specifically, a number of groups have
examined the role of HBV in lipid metabolism, especially In addition to the functional inhibition of a major bile salt
considering the well-established link between hepatocyte transporter, evidence from other studies has suggested
lipids and various stages of the HCV life cycle [241] and that HBV replication may be intimately associated with
the recent identification of a bile salt transporter as a central metabolic pathways. For example, multiple
functional receptor for HBV. transcription factors associated with hepatic metabolic
processes, including HNFs, [244,245] peroxisome proliferator-
The influence of HBV infection on hepatocyte metabolism activated receptors (PPARs), [245-247] and FXR [248-250] can all
was recently brought to the forefront with the identification be recruited to the HBV genome. Moreover, studies in
[33]
of hNTCP, the primary bile salt transporter in hepatocytes, vitro have shown that exogenous addition of bile acids to
as a functional HBV receptor. Interestingly, the binding of HBV-expressing cells can increase HBV replication. [250,251]
HBV, specifically the preS1 domain of L-HBsAg, to hNTCP
directly interferes with the normal function of hNTCP Induction of gluconeogenesis enhances HBV
suggesting competition for binding motifs within the replication, [252] and HBx has been shown to increase
receptor. Furthermore, point mutations in hNTCP that expression of multiple gluconeogenic genes, [253]
abolished binding of preS1 also blocked the ability of potentially contributing to the central role of HBx
the receptor to bind taurocholate, [242] suggesting that by in HBV replication. Recent RNA-seq analyses of HBV-
binding to hNTCP, HBV could dramatically alter hepatic bile expressing Huh7 cells [254] and primary rat hepatocytes [186]
acid uptake. also detected decreased expression of GLUT2, the main
hepatic glucose transporter. Investigation of the effect
Recently, HBV-mediated inhibition of normal hNTCP of fasting glucose levels on HBV replication revealed
function was extended further using a biochemical a link, albeit minor, between the metabolic state of
profiling approach in which human liver chimeric mice the cell and the level of HBV replication, [245] and both
were infected with HBV, and the impact on cholesterol gluconeogenesis and lipogenesis are under the same
metabolism was determined. Indeed, this study was able transcription factor control as HBV replication. [255] Studies
176 Hepatoma Research | Volume 2 | July 1, 2016