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. IMPORTANCEAberrations 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.

Hepatitis B virus molecular biology and pathogenesis

“…[86, 233] In addition, studies have shown that mutant L-HBsAg can activate mTOR signaling, [261–263] ultimately causing increased lipogenesis. [262] …”

Targeted induction ofde novoFatty acid synthesis enhances MDV replication in a COX-2/PGE2αdependent mechanism through EP2 and EP4 receptors engagement

“…The first step towards FA synthesis is the conversion of citric acid into acetyl-CoA by direct phosphorylation of ACLY. Hepatitis B virus (HBV) and HCMV infections activate the expression of ACLY [38, 39], however the enzymatic activity of ACLY is not critical for virus-induced lipogenesis. Virus-infected cells can use glucose carbon for FA synthesis by ACLY from citrate generated in mitochondria and acetyl-CoA synthetase short-chain family member 2 (ACSS2) from acetate [40].…”

Role of Hepatitis B Virus Large Surface Protein in Promoting Activation of Nuclear SREBPs via ER Stress: Implications for Hepatocellular Carcinoma

“…Interestingly, the mRNA expression of lipogenic enzymes in human HCC samples from ten patients were examined and found to be significantly elevated, including the ACL mRNA, compared with surrounding liver tissue that did not show cancer (Yahagi et al, 2005). Western blot analysis of thirty chronic HBV-infected HCC patients revealed that in twenty of these patients, the HCC tissues had increased levels of ACL enzyme protein compared with paired adjacent non-tumor liver tissue (Teng et al, 2015). There has been reports of activation of ACL activity in Hepatitis B virus transgenic mouse liver.…”

“…There has been reports of activation of ACL activity in Hepatitis B virus transgenic mouse liver. In a recent study, Teng et al, 2015 reported that in livers of transgenic mice expressing the pre-S2 deletion mutant of the LS protein of HBV, the ATP citrate lyase gene (ACL) mRNA levels was upregulated in HCC tissues. Western blotting also revealed the presence of higher levels of the ACL enzyme protein compared with the non-transgenic livers.…”

“…The high expression level of SREBP-1 was found to be associated with large tumor size. Western blot analysis was also performed by Teng et al (2015) on HBV-related HCCs taken from 30 human patients. Both SREBP-1 and ACL protein levels were significantly higher in HCC tissues compared with matched adjacent non-cancerous tissue for 20 of the 30 patient samples.…”