title: Activation of ATP citrate lyase by mTOR signal induces disturbed lipid metabolism in hepatitis B virus pre-S2 mutant tumorigenesis.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Chiao-Fang
authors.initials: CF
authors.lastname: Teng
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Wu
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Wen-Chuan
authors.initials: WC
authors.lastname: Hsieh
authors.affiliation: Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Hung-Wen
authors.initials: HW
authors.lastname: Tsai
authors.affiliation: 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.
authors.forename: Ih-Jen
authors.initials: IJ
authors.lastname: Su
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000096:biosynthesis*; D000818:Animals; D063646:Carcinogenesis; D002460:Cell Line; D020869:Gene Expression Profiling; D006514:Hepatitis B Surface Antigens / Q000235:genetics*; D006515:Hepatitis B virus / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology; D054884:Host-Pathogen Interactions; D050356:Lipid Metabolism; D008099:Liver / Q000473:pathology / Q000821:virology; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D006514:Hepatitis B Surface Antigens; D050505:Mutant Proteins; D011498:Protein Precursors; C050807:presurface protein 2, hepatitis B surface antigen; D001275:ATP Citrate (pro-S)-Lyase; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases