A biphasic response pattern of lipid metabolomics in the stage progression of hepatitis B virus X tumorigenesis

Abstract

Metabolic syndrome has closely linked to the development of human hepatocellular carcinoma (HCC). By using the hepatitis B virus (HBV) X (HBx) transgenic mouse model, we studied the dynamic evolution of serum and liver profiles of lipids and global cDNA expression at different stages of HBx tumorigenesis. We observed that the lipid (triglycerides, cholesterol, and fatty acids) profiles revealed a biphasic response pattern during the progression of HBx tumorigenesis: a small peak at early phase and a large peak or terminal switch at the tumor phase. By analyzing cDNA microarray data, the early peak correlated to the oxidative stress and pro-inflammatory response, which then resolved at the middle phase and were followed by the terminal metabolic switch in the tumor tissues. Five lipid metabolism-related genes, the arachidonate 5-lipoxygenase, lipoprotein lipase, fatty acid binding protein 4, 1-acylglycerol-3-phosphate O-acyltransferase 9, and apolipoprotein A-IV were identified to be significantly activated in HBx transgenic HCCs and further validated in human HBV-related HCCs. Inhibition of these lipid genes could reverse the effect of HBx on lipid biosynthesis and suppress HBx-induced cell proliferation in vitro. Our results support the concept that metabolic syndrome plays an important role in HBV tumorigenesis. The dysregulation of lipid metabolic genes may predict the disease progression to HCC in chronic hepatitis B patients.

Identification of novel biomarkers of hepatocellular carcinoma by high‐definition mass spectrometry: Ultrahigh‐performance liquid chromatography quadrupole time‐of‐flight mass spectrometry and desorption electrospray ionization mass spectrometry imaging

“…Several studies have already reported differences in the species of TG in tumor tissues . The major species of SFA and MUFA, palmitic acid (C16:0) and oleic acid (C18:1), were higher in the tumor region, and PUFA, including linoleic acid (C18:2), was lower in the tumor region than in the nontumor region, which was consistent with our results.…”

Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis

“…Analysis of lipid metabolites in HBx transgenic mice showed that arachidonate 5-lipoxygenase, lipoprotein lipase, fatty acid binding protein 4, 1-acylglycerol-3-phosphate O-acyltransferase 9, and apolipoprotein A-IV expression are all induced [353]. Furthermore, HBx-transgenic mice exhibit elevated levels of cholesterol and triglycerides, as well as activated expression of the key transcription factors in lipid homeostasis [353], such as the prolipogenic sterol regulatory element binding protein 1 (SREBP-1), liver X receptor [354], C/EBP1 and peroxisome proliferator-activated receptor γ (PPARγ) [355].…”

“…Furthermore, HBx-transgenic mice exhibit elevated levels of cholesterol and triglycerides, as well as activated expression of the key transcription factors in lipid homeostasis [353], such as the prolipogenic sterol regulatory element binding protein 1 (SREBP-1), liver X receptor [354], C/EBP1 and peroxisome proliferator-activated receptor γ (PPARγ) [355]. In turn, liver PPAR-γ and SREBP-1c up-regulation in parallel with PPAR-α down-regulation enhance de novo lipogenesis and reduce fatty acid oxidation [356].…”

Liver regeneration accelerates hepatitis B virus‐related tumorigenesis of hepatocellular carcinoma

“…Recently, the ground glass hepatocytes, which harbor two HBV oncoproteins, the pre-S mutant surface antigen and the hepatitis B X protein (HBx), have been proposed as the precursor lesions of HCC (Wu et al, 2014;Yen et al, 2016). HBx is an etiologic factor of HBV-related hepatocarcinogenesis through its multiple functions in regulation of cell cycle, cell proliferation, lipid metabolism, signal transduction, and gene transcription (Arbuthnot et al, 2000;Chisari et al, 1989;Teng et al, 2016). Overexpression of HBx can cause tumorigenicity in an HBx transgenic mouse model (Newell et al, 2008).…”