Peretinoin，Acyclic Retinoid，抑制乙型肝炎病毒复制抑制鞘氨醇代

StephenW

Int J Mol Sci. 2018 Jan 23;19(2). pii: E108. doi: 10.3390/ijms19020108.
Peretinoin, an Acyclic Retinoid, Inhibits Hepatitis B Virus Replication by Suppressing Sphingosine Metabolic Pathway In Vitro.Murai K1,2, Shirasaki T3,4, Honda M5,6, Shimizu R7,8, Shimakami T9, Nakasho S10,11, Shirasaki N12, Okada H13, Sakai Y14, Yamashita T15, Kaneko S16.
Author information
1Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8641, Japan. [email protected].2Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa 920-0942, Japan. [email protected].3Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8641, Japan. [email protected].4Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa 920-0942, Japan. [email protected].5Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8641, Japan. [email protected].6Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa 920-0942, Japan. [email protected].7Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8641, Japan. [email protected].8Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa 920-0942, Japan. [email protected].9Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8641, Japan. [email protected].10Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8641, Japan. [email protected].11Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa 920-0942, Japan. [email protected].12Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8641, Japan. [email protected].13Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8641, Japan. [email protected].14Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8641, Japan. [email protected].15Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8641, Japan. [email protected].16Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8641, Japan. [email protected].

AbstractHepatocellular carcinoma (HCC) frequently develops from hepatitis C virus (HCV) and hepatitis B virus (HBV) infection. We previously reported that peretinoin, an acyclic retinoid, inhibits HCV replication. This study aimed to examine the influence of peretinoin on the HBV lifecycle. HBV-DNA and covalently closed circular DNA (cccDNA) were evaluated by a qPCR method in HepG2.2.15 cells. Peretinoin significantly reduced the levels of intracellular HBV-DNA, nuclear cccDNA, and HBV transcript at a concentration that did not induce cytotoxicity. Conversely, other retinoids, such as 9-cis, 13-cis retinoic acid (RA), and all-trans-retinoic acid (ATRA), had no effect or rather increased HBV replication. Mechanistically, although peretinoin increased the expression of HBV-related transcription factors, as observed for other retinoids, peretinoin enhanced the binding of histone deacetylase 1 (HDAC1) to cccDNA in the nucleus and negatively regulated HBV transcription. Moreover, peretinoin significantly inhibited the expression of SPHK1, a potential inhibitor of HDAC activity, and might be involved in hepatic inflammation, fibrosis, and HCC. SPHK1 overexpression in cells cancelled the inhibition of HBV replication induced by peretinoin. This indicates that peretinoin activates HDAC1 and thereby suppresses HBV replication by inhibiting the sphingosine metabolic pathway. Therefore, peretinoin may be a novel therapeutic agent for HBV replication and chemoprevention against HCC.


KEYWORDS: HDAC1; SPHK1; acyclic retinoid; hepatitis B virus

PMID:29360739DOI:10.3390/ijms19020108

StephenW

Int J Mol Sci。 2018年1月23日; 19（2）。 pii：E108。 doi：10.3390 / ijms19020108。
Peretinoin，Acyclic Retinoid，抑制乙型肝炎病毒复制抑制鞘氨醇代谢途径体外。
Murai K1,2，Shirasaki T3,4，Honda M5,6，Shimizu R7,8，Shimakami T9，Nakasho S10,11，Shirasaki N12，Okada H13，Sakai Y14，Yamashita T15，Kaneko S16。
作者信息

1
    金泽大学医学研究科消化科，日本金泽920-8641。 [email protected]。
2
    日本金泽920-0942金泽大学医学研究科先进医疗技术系。 [email protected]。
3
    金泽大学医学研究科消化科，日本金泽920-8641。 [email protected]。
4
    日本金泽920-0942金泽大学医学研究科先进医疗技术系。 [email protected]。
五
    金泽大学医学研究科消化科，日本金泽920-8641。 [email protected]。
6
    日本金泽920-0942金泽大学医学研究科先进医疗技术系。 [email protected]。
7
    金泽大学医学研究科消化科，日本金泽920-8641。 [email protected]。
8
    日本金泽920-0942金泽大学医学研究科先进医疗技术系。 [email protected]。
9
    金泽大学医学研究科消化科，日本金泽920-8641。 [email protected]。
10
    金泽大学医学研究科消化科，日本金泽920-8641。 [email protected]。
11
    日本金泽920-0942金泽大学医学研究科先进医疗技术系。 [email protected]。
12
    金泽大学医学研究科消化科，日本金泽920-8641。 [email protected]。
13
    金泽大学医学研究科消化科，日本金泽920-8641。 [email protected]。
14
    金泽大学医学研究科消化科，日本金泽920-8641。 [email protected]。
15
    金泽大学医学研究科消化科，日本金泽920-8641。 [email protected]。
16
    金泽大学医学研究科消化科，日本金泽920-8641。 [email protected]。

抽象

肝细胞癌（HCC）经常从丙型肝炎病毒（HCV）和乙型肝炎病毒（HBV）感染发展而来。我们以前报道，peretinoin，无环类维生素A，抑制HCV复制。本研究旨在探讨peretinoin对HBV生命周期的影响。在HepG2.2.15细胞中通过qPCR方法评估HBV-DNA和共价闭合环状DNA（cccDNA）。在不诱导细胞毒性的浓度下，Peretinoin显着降低细胞内HBV-DNA，核cccDNA和HBV转录物的水平。相反，其他类视色素，如9-顺式，13-顺式视黄酸（RA）和全反式视黄酸（ATRA），对乙肝病毒的复制没有影响或增加。从机制上看，尽管peretinoin增加了HBV相关转录因子的表达，但是与其他类维生素A类似，peretinoin增强了组蛋白去乙酰化酶1（HDAC1）与核内cccDNA的结合并负调节HBV转录。此外，peretinoin可显着抑制HDAC活性的潜在抑制剂SPHK1的表达，并可能参与肝脏炎症，纤维化和HCC。 SPHK1在细胞中的过度表达取消了由peretinoin诱导的HBV复制的抑制。这表明，peretinoin激活HDAC1，从而通过抑制鞘氨醇代谢途径抑制HBV复制。因此，peretinoin可能是HBV复制和化学预防HCC的新型治疗剂。
关键词：

HDAC1; SPHK1;无环类视黄醇;乙肝病毒

结论：
    29360739
DOI：
    10.3390 / ijms19020108