Open AccessSuppression of silent information regulator 1 activity in noncancerous tissues of hepatocellular carcinoma: Possible association with non‐B non‐C hepatitis pathogenesis
Author(s) -
Konishi Hideyuki,
Shirabe Ken,
Nakagawara Hidekazu,
Harimoto Norifumi,
Yamashita YoIchi,
Ikegami Toru,
Yoshizumi Tomoharu,
Soejima Yuji,
Oda Yoshinao,
Maehara Yoshihiko
Publication year - 2015
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12653
Subject(s) - hepatocellular carcinoma , nad+ kinase , hepatitis , regulator , nicotinamide , nicotinamide adenine dinucleotide , biology , nicotinamide phosphoribosyltransferase , immunology , cancer research , medicine , biochemistry , enzyme , gene
Silent information regulator 1 ( SIRT 1) is a nicotinamide adenine dinucleotide ( NAD + )‐dependent protein deacetylase. In mice, mS irt1 deficiency causes the onset of fatty liver via regulation of the hepatic nutrient metabolism pathway. In this study, we demonstrate SIRT 1 expression, activity and NAD + regulation using noncancerous liver tissue specimens from hepatocellular carcinoma patients with non‐B non‐C ( NBNC ) hepatitis. SIRT 1 expression levels were higher in NBNC patients than in healthy donors, while SIRT 1 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. SIRT 1 expression was associated with HIF 1 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 CXCL 10 and MCP ‐1. These inductions were suppressed in rich NAD + condition, and by SIRT 1 activator treatment. In conclusion, hepatic SIRT 1 activity was repressed in NBNC patients, and normalization of NAD + amounts and activation of SIRT 1 could improve the inflammatory condition in the liver of NBNC hepatitis patients.