國家衛生研究院 NHRI:Item 3990099045/8351

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Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/8351

Title:	Activation of ATP citrate lyase by mTOR signal induces disturbed lipid metabolism in hepatitis B virus pre-S2 mutant tumorigenesis
Authors:	Teng, CF;Wu, HC;Hsieh, WC;Tsai, HW;Su, IJ
Contributors:	Division of Infectious Diseases
Abstract:	The development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) has been found to be associated with disturbed lipid metabolism. To elucidate the role of lipid metabolism in HBV tumorigenesis, we investigated the dynamic pattern of lipid metabolism in HBV pre-S2 mutant-induced tumorigenesis. Lipid and gene expression profiles were analyzed in an in vitro culture system and in transgenic mice livers harboring HBV pre-S2 mutant. The pre-S2 mutant transgenic livers showed a biphasic pattern of lipid accumulation, starting from mild fatty change in early (1 month) transgenic livers, which subsided and then remarkably increased in HCC tissues. This biphasic pattern was synchronized with ATP citrate lyase (ACLY) activation. Further analyses revealed that the pre-S2 mutant initiated an endoplasmic reticulum (ER) stress-dependent mammalian target of rapamycin (mTOR) signal cascade. The pre-S2 mutant-induced mTOR signal activated the sterol regulatory element binding transcription factor 1 (SREBF1) to upregulate ACLY, which then activated the fatty acid desaturase 2 (FADS2) mediated through ACLY-dependent histone acetylation. Such an ER stress-dependent mTOR signal cascade is also important for the proliferation of hepatocytes in vitro and is further validated in HBV-related HCC tissues. IMPORTANCE: Aberrations of lipid metabolism frequently occur in chronic HBV infection. Our results provide the potential mechanism of disturbed lipid metabolism in HBV pre-S2 mutant-induced tumorigenesis, which should be valuable for the design of HCC chemoprevention in high-risk HBV carriers.
Date:	2015-01
Relation:	Journal of Virology. 2015 Jan;89(1):605-614.
Link to:	http://dx.doi.org/10.1128/jvi.02363-14
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-538X&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000347176100051
Cited Times(Scopus):	http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84919429845
Appears in Collections:	[Ih-Jen Su(2002-2015)] Periodical Articles

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