Hepatitis B virus (HBV) replicates by the reverse transcription of the viral 3.5kb pregenomic RNA. Therefore the level of expression of this transcript in the liver is a primary determinant of HBV biosynthesis. In vivo neonatal transcription of the HBV 3.5kb pregenomic RNA is developmental regulated by hepatocyte nuclear factor 4α (HNF4α). In addition, viral biosynthesis in non-hepatoma cells can be supported directly by this nuclear receptor. However HBV transcription and replication can be supported by additional nuclear receptors including the retinoid X receptor α/peroxisome proliferator-activated receptor α (RXRα/PPARα), retinoid X receptor α/farnesoid X receptor α (RXRα/FXRα), liver receptor homolog 1 (LRH1) and estrogen-related receptors (ERR) in non-hepatoma cells. Therefore during neonatal liver development, HNF4α may progressively activate viral transcription and replication by binding directly to the proximal HNF4α recognition sequence within the nucleocapsid promoter. Alternatively, HNF4α may support viral biosynthesis in vivo indirectly by activating a network of liver-enriched nuclear receptors that, in combination, direct HBV 3.5kb pregenomic RNA transcription and replication.
In natural infection, hepatitis B virus (HBV) transcription and replication is essentially restricted to the hepatocytes in the livers of humans and a limited number of primates (15,19,33,36,41). HBV tropism is probably restricted at the level of entry by the viral receptor, which likely has a limited tissue distribution (10, 33). In addition, transcription of the viral genome limits HBV biosynthesis to cells expressing the nuclear receptors required for viral pregenomic RNA synthesis and replication (13,40). The nuclear receptors present in hepatocytes that regulate HBV transcription include both liganddependent and orphan nuclear receptors which lack known ligands (16,22,30,40). Long-chain fatty acids are ligands for peroxisome proliferator-activated receptor ␣ (PPAR␣), which links HBV biosynthesis to energy homeostasis (9). Bile acids are ligands for farnesoid X receptor ␣ (FXR␣), further linking HBV biosynthesis to lipid metabolism (29, 30). Hepatocyte nuclear factor 4␣ (HNF4␣) and estrogen-related receptor (ERR) are orphan nuclear receptors, which like PPAR␣ and FXR␣ can display alteration in transcriptional activities in response to the coactivator peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC1␣) and the corepressor small heterodimer partner (SHP) (1, 23). PGC1␣ is critical for the activation of liver gluconeogenesis and therefore couples HBV transcription and replication to liver carbohydrate metabolism and whole-body energy homeostasis (43). SHP expression is activated by bile acids via FXR␣ and tumor necrosis factor ␣ through AP1, leading to the inhibition of the activities of multiple nuclear receptors (6,11,14,24). Therefore, SHP may regulate HBV biosynthesis in response to changing lipid metabolism or inflammatory signals within the liver (28).Several nuclear receptors expressed in the liver have been shown to support HBV biosynthesis in nonhepatoma cell lines (see Fig. 1 to 6) (27a, 40). However, it is unclear which of these nuclear receptors are critical to supporting viral transcription and replication in hepatocytes in vivo. Conditional deletion of HNF4␣ in the liver of neonatal HBV transgenic mice demonstrated that this nuclear receptor was essential for viral biosynthesis (21). However, the early developmental loss of HNF4␣ is associated with decreased expression of a variety of additional nuclear receptors capable of supporting viral biosynthesis. Therefore, it is unclear if the loss in HBV transcription and replication observed in the liver-specific HNF4␣-null HBV transgenic mouse is due directly to the loss of HNF4␣ or to the indirect effects on other nuclear receptors (18). Similarly, it is apparent that hepatoma cells can support HBV biosynthesis, but it has not been established which transcription factors present in these cells, but not in nonhepatoma cells, are responsible for supporting viral pregenomic RNA synthesis (4,39,40).Given the importance of nuclear receptors and their associated coactivators and corepressors to liver energy homeostasis,
Hepatitis B virus (HBV) replicates efficiently in hepatocytes in vivo and in hepatoma cells in culture because these cells have the appropriate composition of transcription factors to support the expression of the 3.5-kb viral pregenomic transcript, which is reverse transcribed to generate the relaxed circular genomic DNA present in infectious viral particles (4,11,26,27,29). In contrast, HBV transcription and replication does not occur in the majority of nonhepatic tissues in vivo or nonhepatoma cell lines in culture due to the absence of transcription of the 3.5-kb viral pregenomic RNA (11,27). However, complementation of nonhepatoma cells with several nuclear receptors but not other liver-enriched transcription factors leads to robust HBV transcription and replication (see Fig. 1 to 3) (18a, 27). These observations have led to the suggestion that transcriptional regulation of HBV biosynthesis is an important determinant of viral tropism, which may be just as significant as the presumptive cell type-specific expression of the viral receptor (22, 27).The molecular characterization of the various steps in the viral life cycle has been largely elucidated, utilizing human hepatoma cell lines (10, 24). In particular, the human hepatoma cell lines HepG2 and Huh7 have been utilized because they can support viral replication when transfected with genomic HBV DNA (4, 26). In addition, these two cell lines lack integrated HBV DNA which is commonly associated with other human hepatoma cell lines (4, 26, 28). As products from integrated HBV sequences might have unidentified effects on viral transcription and replication, the majority of studies aimed at understanding the various aspects of HBV transcription and replication have utilized HepG2 and Huh7 cells. The majority of observations using these two cell lines have been similar with regard to HBV biosynthesis, leading to the general assumption that they are essentially equivalent with respect to HBV biosynthesis (4,24,26). However, it is clear that these hepatoma cell lines are morphologically distinct and, consequently, probably display distinct patterns of gene regulation.Recent studies have indicated that 3.5-kb pregenomic HBV RNA expression and viral replication are regulated by a variety of nuclear receptors (see Fig. 1 to 3) (18a, 27). The observation that several nuclear receptors can potentially contribute to the level of viral biosynthesis raised the critical question of their relative importance both in vivo and in cell culture. In an attempt to address this issue, the effect of expressing the coactivator peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC1␣) and the corepressor small heterodimer partner (SHP) on HBV transcription and replication in both human hepatoma and nonhepatoma cells was quantitatively evaluated with a view to establishing the potential role of distinct nuclear receptors in regulating viral biosynthesis in the HepG2 and Huh7 cells. This analysis demonstrated that each nuclear receptor displayed a unique pattern of responsi...
Hepatitis B virus (HBV) transcription and replication are essentially restricted to hepatocytes because liver-enriched transcription factors govern viral RNA synthesis. The level of transcription from the HBV promoters depends on both the transcription factors binding to these regulatory sequence elements and their ability to recruit coactivators capable of mediating assembly of the transcription preinitiation complex containing RNA polymerase II. Nuclear receptors are a primary determinant of HBV pregenomic RNA synthesis and, hence, viral replication. Peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC1␣) enhances the activity of nuclear receptors and, consequently, HBV biosynthesis. PGC1␣ is also an important target of signal transduction pathways involved in hepatic glucose and lipid homeostasis, suggesting that this coactivator may have an important role in modulating HBV biosynthesis under various physiological conditions. Consistent with this suggestion, v-akt murine thymoma viral oncogene homolog/protein kinase B (AKT/PKB) is shown to modulate PGC1␣ activity and, hence, HBV transcription and replication in a cell line-specific manner. In addition, AKT can modulate HBV replication in some but not all cell lines at a posttranscriptional step in the viral life cycle. These observations demonstrate that growth and nutritional signals have the capacity to influence viral production, but the magnitude of these effects will depend on the precise cellular context in which they occur.Studies of hepatitis B virus (HBV) replication have demonstrated that viral DNA synthesis occurs by the reverse transcription of viral pregenomic 3.5-kb RNA (45, 56). Therefore, it is apparent that the level of transcription from the HBV nucleocapsid promoter is a major determinant of viral biosynthesis (48). The regulatory elements within the HBV nucleocapsid promoter have been analyzed in detail in an attempt to identify the transcription factors controlling viral RNA synthesis (18,47). Indeed, the HBV nucleocapsid promoter binds a variety of liver-enriched and ubiquitous transcription factors that probably contribute to the level of viral pregenomic 3.5-kb RNA synthesis to different degrees depending on the physiological state of the infected hepatocyte (18, 47). Utilizing nonhepatoma cells that do not support viral pregenomic 3.5-kb RNA synthesis or HBV replication, complementation studies with individual liver-enriched transcription factors demonstrated that only nuclear receptors were capable of rescuing viral biosynthesis in the absence of additional factors (38, 48). These observations indicated that nuclear receptors may have a unique role in governing HBV biosynthesis during natural infection. Indeed, in vivo analysis using the transgenic mouse model of chronic HBV infection demonstrated that viral RNA and DNA synthesis was completely dependent on the nuclear receptor hepatocyte nuclear factor 4␣ (HNF4␣) (22).Nuclear receptors and their coactivators within the liver are important regulators of energy homeostasis...
Summary Sirtuin enzymes depend on NAD+ to catalyze protein deacetylation. Therefore, the lowering of NAD+ during aging leads to decreased sirtuin activity and may speed up aging processes in laboratory animals and humans. In this study, we used a genetic screen to identify two mutations in the catalytic domain of yeast Sir2 that allow the enzyme to function in an NAD+-depleted environment. These mutant enzymes give rise to a significant increase of yeast replicative lifespan and increase deacetylation by the Sir2 ortholog, SIRT1, in mammalian cells. Our data suggest that these mutations increase the stability of the conserved catalytic sirtuin domain, thereby increasing the catalytic efficiency of the mutant enzymes. Our approach to identifying sirtuin mutants that permit function in NAD+-limited environments may inform the design of small molecules that can maintain sirtuin activity in aging organisms.
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