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J Virol. 2015 Jan;89(1):605-14. doi: 10.1128/JVI.02363-14. Epub 2014 Oct 22.

Activation of ATP citrate lyase by mTOR signal induces disturbed lipid metabolism in hepatitis B virus pre-S2 mutant tumorigenesis.

Author information

1
National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan.
2
Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan.
3
National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan Institute of Basic Medical Sciences, National Cheng Kung University College of Medicine, Tainan, Taiwan suihjen@nhri.org.tw.

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 mouse 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) signalling 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 also is 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 a 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.

PMID:
25339766
PMCID:
PMC4301163
DOI:
10.1128/JVI.02363-14
[Indexed for MEDLINE]
Free PMC Article

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