Page 186 - Read Online

have linked metabolic changes to effects of HBV proteins. HBx expression. Specifically, inhibition of apoptosis was
For example, some of the earliest functions attributed linked to HBx-mediated activation of NFκB; however,
to HBx involved its regulation of metabolic pathways, when activation of NFκB was blocked, HBx induced
such as HBx-mediated activation of the Ras-Raf-MAPK apoptosis through pathways involving the mitochondria
pathway, [256,257] a central pathway involved in the permeability transition pore (MPTP), a critical pore that
response to nearly all changes that affect metabolism. [258] spans the inner mitochondrial and outer mitochondrial
Protein kinase C (PI3K) is also activated by HBx, [259,260] membranes and affects numerous mitochondrial
which correlates with recent results suggesting HBV functions, including mitochondrial control of
and HBx activate the PI3K/Akt pathway, reducing HBV apoptosis. Whether HBV, through functions of HBx,
[83]
replication. [86,233] In addition, studies have shown that regulates apoptosis as a mechanism for regulating
mutant L-HBsAg can activate mTOR signaling, [261-263] viral replication or enhancing viral spread is currently
ultimately causing increased lipogenesis. [262] unknown. Although activation of apoptosis may impact
both viral spread, [280,281] and immune evasion, recent
[93]
When considered in combination, these studies support evidence suggests that alteration of apoptosis during
the characterization of HBV as a “metabolovirus”, and HBV infection is unlikely to impact viral spread. [282]
HBV responds to and causes significant metabolic Due to the regenerative nature of hepatocytes, it is
changes in the cell. While the clinical impact of this also possible that the impact of HBV on apoptosis may
altered metabolic regulation remains unknown, some fluctuate during the course of infection, as regenerating
studies have suggested that HBV can “help” reduce hepatocytes have different active signaling pathways
fatty liver disease. [264] The overall link between HBV and than quiescent cells, and these could have differing
metabolic syndrome remains less clear; however, studies influences on apoptotic stimuli. [280,283,284] Interestingly,
that consider the impact of direct infection through both the activation and the inactivation of apoptosis
a major metabolic receptor may help to enhance our could be playing a role in the long-term development
understanding of the link between HBV and metabolic of HBV-associated HCC: enhanced regeneration
pathways, and how this relationship may impact the associated with HBV-mediated activation of apoptosis
metabolic state of the liver and the development of HBV- could lead to selection of apoptosis-resistant cells, [285]
associated disease and HCC. while inhibition of apoptosis could lead to unchecked
proliferation and the accumulation of transforming
HBV and apoptosis mutations. [93] Although the exact mechanisms that
Despite the many studies that have investigated the effect underlie HBV and HBx regulation of apoptosis remain
of an HBV infection and expression of HBV proteins on incompletely understood, the cellular impact of altered
hepatocyte pro- and anti-apoptotic signaling pathways, apoptotic signaling could significantly contribute to the
the interplay of an HBV infection and hepatocyte downstream development of HBV-associated disease
apoptotic signaling pathways remains incompletely and HCC.
understood. Because an HBV infection is non-cytopathic,
it would be expected that HBV either inhibits or has little HBV and microRNAs
effect on apoptotic pathways. Evidence has suggested, Potentially spurred by the discovery of the required
however, an HBV-mediated effect on cellular apoptosis role of miR-122 in successful HCV replication, [286,287]
that is cell-type- or cell-context-dependent. Some of multiple groups have begun to investigate how cellular
these differing effects can be attributed to HBx activities, miRNAs may impact various aspects of HBV biology, and
which often have divergent functions depending on alternatively, how HBV may impact the expression of
context. In the case of apoptosis, some studies have cellular miRNAs. These effects have been reviewed in
shown that HBx can inhibit apoptosis [86,265-269] or have more detail elsewhere. [230,288]
no effect on apoptosis, [99,270,271] while other studies have
shown that HBx can activate apoptotic pathways [272-276] While a wide range of cellular miRNAs has been
or sensitize cells to pro-apoptotic stimuli. [277-279] The investigated for their role in regulating or being regulated
context-dependent apoptotic effects of HBx were clearly by HBV, none has been studied as extensively as miR-
shown by studies demonstrating that HBx sensitized 122. This miRNA, which makes up 50-70% of the total
dedifferentiated hepatocytes to apoptosis, while HBx- miRNA pool in hepatocytes [289,290] has been shown to have
expressing hepatocytes that remained differentiated many different roles in the context of HBV replication.
were resistant to apoptotic stimuli. [279] This underscores Although conflicting reports do exist, it seems that miR-
the importance of using relevant cell systems for studying 122 functions as an antiviral miRNA, potentially through
the cellular impact of HBV replication and protein multiple mechanisms. These mechanisms include direct
expression on cell physiology. HBx was also shown targeting of viral RNAs through miR-122 recognition sites
to have divergent apoptotic functions in the context in the HBV genome [291,292] and altered miR-122-mediated
of HBV replication. Studies in primary hepatocytes regulation of cellular factors involved in regulation of
demonstrated that HBx can have both a pro- and anti- HBV replication, such as heme oxygenase-1, [293] cyclin
apoptotic effect, depending on the cellular context of G1, [294,295] and pituitary tumor-transforming gene 1
Hepatoma Research | Volume 2 | July 1, 2016 177