Suppression of silent information regulator 1 activity in noncancerous tissues of hepatocellular carcinoma: Possible association with non-B non-C hepatitis pathogenesis.
Suppression of silent information regulator 1 activity in noncancerous tissues of hepatocellular carcinoma: Possible association with non-B non-C hepatitis pathogenesis.
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DOI：
10.1111/cas.12653
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发表时间：
2015-05
期刊：
影响因子：
5.7
通讯作者：
Maehara Y
中科院分区：
文献类型：
--
作者：
Konishi H;Shirabe K;Nakagawara H;Harimoto N;Yamashita Y;Ikegami T;Yoshizumi T;Soejima Y;Oda Y;Maehara Y
沉默信息调节因子1 （SIRT1）是一种烟酰胺腺嘌呤二核苷酸（NAD+）依赖的蛋白去乙酰化酶。在小鼠中，mSirt1缺乏通过调节肝脏营养代谢途径导致脂肪肝的发病。在这项研究中，我们利用肝细胞癌合并非乙型非丙型肝炎（NBNC）患者的非癌性肝组织标本，研究了SIRT1的表达、活性和NAD+的调节。NBNC患者的SIRT1表达水平高于健康供体，而NBNC患者的SIRT1组蛋白H3K9去乙酰化活性受到抑制。在肝炎患者的肝脏中，观察到NAD+的数量及其调节酶烟酰胺磷酸核糖基转移酶的表达水平下降，这导致SIRT1活性受到抑制。在NBNC肝癌和肝癌细胞系中，SIRT1的表达与HIF1蛋白积累有关。这些结果可能表明NBNC肝炎肝脏暴露于缺氧条件下。在HepG2细胞中，缺氧诱导炎症趋化因子，如CXCL10和MCP-1。这些诱导在富含NAD+的条件下和SIRT1激活剂处理下被抑制。综上所述，NBNC患者肝脏SIRT1活性受到抑制，NAD+量的正常化和SIRT1的激活可以改善NBNC肝炎患者肝脏炎症状况。
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.
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DOI：
10.1126/science.1231097
发表时间：
2013-03-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hubbard BP;Gomes AP;Dai H;Li J;Case AW;Considine T;Riera TV;Lee JE;E SY;Lamming DW;Pentelute BL;Schuman ER;Stevens LA;Ling AJ;Armour SM;Michan S;Zhao H;Jiang Y;Sweitzer SM;Blum CA;Disch JS;Ng PY;Howitz KT;Rolo AP;Hamuro Y;Moss J;Perni RB;Ellis JL;Vlasuk GP;Sinclair DA
通讯作者：
Sinclair DA
DOI：
10.1152/ajpgi.90358.2008
发表时间：
2008-10-01
影响因子：
4.5
作者：
Ajmo, Joanne M.;Liang, Xiaomei;You, Min
通讯作者：
You, Min
影响因子：
64.8
作者：
Rodgers, JT;Lerin, C;Puigserver, P
通讯作者：
Puigserver, P
影响因子：
3.3
作者：
Lin, Hsiu-Ching;Chen, Yi-Fan;Tsai, Ting-Fen
通讯作者：
Tsai, Ting-Fen
影响因子：
5.7
作者：
Peck, Barrie;Chen, Chun-Yuan;Lam, Eric W. -F.
通讯作者：
Lam, Eric W. -F.