Sirtuins (SIRTs), NAD+-dependent, class III histone deacetylases, are important in cellular processes, including cellular apoptosis, metabolism, stress resistance, and genomic stability. Various liver defects are associated with SIRTs. Among 7 mammalian SIRTs, SIRTs 1–7, the nuclear SIRT1, the cytoplasmic SIRT2, and the mitochondrial SIRT3 are well-studied. However, the mitochondrial SIRT4 and SIRT5 and the nuclear SIRT6 and SIRT7 are relatively less studied. Recent data suggests that mitochondrial SIRTs protect against the development of age-related chronic diseases. SIRT4, an ADP-dependent NAD+ transferase, regulates insulin secretion, fatty acid oxidation, and other cellular metabolic functions, such as glutamine metabolism. Recently, SIRT4 was suggested to act as a tumor-suppressor and to involve in hepatocellular carcinoma (HCC). Nonetheless, there is no conclusion yet on whether SIRT4 has either positive or negative impact on HCC. Since hepatitis B virus (HBV) infection can cause primary HCC, I investigated whether SIRT 4 has any role(s) on HBV replication, Among 2 isoforms of SIRT4, I focused on SIRT4 isoform 1 (SIRT4.1), a main isoform of SIRT4. SIRT4 was over-expressed in HBV replicating cells. I found that SIRT4.1 WT over-expression reduced HBV mRNA transcription, HBc protein level, core particle formation, replicative intermediate HBV DNA, also known as relaxed circular, double-stranded linear, and single-stranded DNA, synthesis in HBV replicating-HepG2 and -Huh7 cells. Additionally, I discovered that the endogenous SIRT4 level was increased in HBV replicating-HepG2 cells and the endogenous SIRT4 level was shown to be increased in biopsied HBV-associated HCC tumor tissues compared to adjacent non-tumor tissues. Furthermore unlike SIRT4.1 WT, the SIRT4.1 catalytically inactive H161Y mutant did not reduce HBV replication. I found that when overexpressed SIRT4.1 down-regulates HBV replication, AMPK, a known down-regulator of HBV replication, was activated. Moreover co-immunoprecipitation experiment reveals the interaction between SIRT4.1 and AMPK, suggesting that SIRT4.1 is involved in the restriction of HBV replication through an activation of AMPK. Even though further studies are required, our results can reveal a new approach of controlling hepatitis B on the molecular basis.
