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. 2015 May;106(5):542-9.
doi: 10.1111/cas.12653. Epub 2015 Apr 1.

Suppression of silent information regulator 1 activity in noncancerous tissues of hepatocellular carcinoma: Possible association with non-B non-C hepatitis pathogenesis

Hideyuki Konishi  1   2 , Ken Shirabe  1 , Hidekazu Nakagawara  1 , Norifumi Harimoto  1 , Yo-Ichi Yamashita  1 , Toru Ikegami  1 , Tomoharu Yoshizumi  1 , Yuji Soejima  1 , Yoshinao Oda  3 , Yoshihiko Maehara  1
Affiliations

Suppression of silent information regulator 1 activity in noncancerous tissues of hepatocellular carcinoma: Possible association with non-B non-C hepatitis pathogenesis

Hideyuki Konishi et al. Cancer Sci. 2015 May.

Abstract

Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD(+) )-dependent protein deacetylase. In mice, mSirt1 deficiency causes the onset of fatty liver via regulation of the hepatic nutrient metabolism pathway. In this study, we demonstrate SIRT1 expression, activity and NAD(+) regulation using noncancerous liver tissue specimens from hepatocellular carcinoma patients with non-B non-C (NBNC) hepatitis. SIRT1 expression levels were higher in NBNC patients than in healthy donors, while SIRT1 histone H3K9 deacetylation activity was suppressed in NBNC patients. In the liver of hepatitis patients, decreased NAD(+) amounts and its regulatory enzyme nicotinamide phosphoribosyltransferase expression levels were observed, and this led to inhibition of SIRT1 activity. SIRT1 expression was associated with HIF1 protein accumulation in both the NBNC liver and liver cancer cell lines. These results may indicate that the NBNC hepatitis liver is exposed to hypoxic conditions. In HepG2 cells, hypoxia induced inflammatory chemokines, such as CXCL10 and MCP-1. These inductions were suppressed in rich NAD(+) condition, and by SIRT1 activator treatment. In conclusion, hepatic SIRT1 activity was repressed in NBNC patients, and normalization of NAD(+) amounts and activation of SIRT1 could improve the inflammatory condition in the liver of NBNC hepatitis patients.

Keywords: Nicotinamide adenine dinucleotide; nicotinamide phosphoribosyltransferase; non-B non-C hepatitis; non-alcoholic steatohepatitis; silent information regulator 1.

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Figures

Fig 1
Fig 1
Silent information regulator 1 (SIRT1) expression and histone acetylation in the livers. (a) Comparison of hepatic SIRT1 mRNA expression levels between healthy donors, non-B non-C (NBNC), hepatitis B virus (HBV) and hepatitis C virus (HCV) patients. (b) Hepatic SIRT1 protein expression in NBNC patients determined by immunohistochemistry (IHC). Representative images of positive sections (left panels) and negative sections (right panel). (c) Comparison of SIRT1 positive tissue rates by IHC in liver between NBNC and HCV. (d) Comparison of intrahepatic H3K9 relative acetylation levels between healthy donors, NBNC, HBV and HCV patients. H3K9 relative acetylation is determined by calculating the acetylated-histone H3K9/total histone H3 ratio.
Fig 2
Fig 2
Suppression of nicotinamide phosphoribosyltransferase (NAMPT) expression and NAD/NADH ratio in liver of hepatitis. (a) Comparison of hepatic NAMPT mRNA expression levels between healthy donors, non-B non-C (NBNC), hepatitis B virus (HBV) and hepatitis C virus (HCV) patients. (b) Comparison of hepatic NMNAT1 mRNA expression levels between healthy donors and NBNC patients. (c) Comparison of the intrahepatic NAD+/NADH ratios between healthy donors and hepatitis patients, including NBNC (n = 6), HBV (n = 8) and HCV (n = 2). n.s., Not significant.
Fig 3
Fig 3
Silent information regulator 1 (SIRT1) expression in hypoxic condition. (a) HepG2 cells were treated with 50 μM transferrin (TF) or 100 μM deferoxamine (DFX) for 24 h. SIRT1 and HIF1α protein expression levels were detected by western blotting (left panels). Total RNA was extracted and SIRT1 mRNA was measured by real-time RT-PCR (right graph). Relative expression of non-treated cells (NT) is shown. (b, c) HepG2 cells were cultured in the hypoxic condition (1% O2) for 6, 12 and 24 h. (b) SIRT1 and HIF1α protein expression levels in cells were detected by western blotting. (c) Total RNA was extracted and SIRT1 mRNA was measured by real-time RT-PCR. Relative expression of normoxia-cultured (21% O2) cells is shown. (d) Hep3B cells were cultured in the hypoxic condition for 24 and 48 h. SIRT1 and HIF1α protein expression levels in cells were detected by western blotting.
Fig 4
Fig 4
Silent information regulator 1 (SIRT1) activation and hypoxia-induced chemokine expression. (a) Comparison of hepatic CXCL10 mRNA expression levels between healthy donors and non-B non-C (NBNC) patients. (b) HepG2 cells were cultured in the hypoxic condition in high glucose (25 mM) and low glucose (5 mM) medium for 24 h. The intracellular NAD+/NADH ratio is shown. (c) Hypoxia-induced CXCL10 expression in HepG2 cells is shown. Cells were cultured in the hypoxic condition in high glucose, low glucose or low glucose with 1 μM SRT1720 containing medium for 24 or 48 h. (d) Tumor necrosis factor (TNF)-induced CXCL10 expression levels in HepG2 cells is shown. Cells were cultured in 1 ng/mL TNF or TNF with 1 μM SRT1720 containing medium for 24 h. (e) Hypoxia-induced MCP-1 expression in HepG2 cells is shown. Cells were cultured in the hypoxic condition in high glucose, low glucose or low glucose with 1 μM SRT1720 containing medium for 24 or 48 h. n.s., Not significant.
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