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Microarray Analysis Provides New Insights Into the Function of Apolipoprotein O in Hepg2 Cell Line Chen-Lu Wu, Shui-Ping Zhao* and Bi-Lian Yu*

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Microarray Analysis Provides New Insights Into the Function of Apolipoprotein O in Hepg2 Cell Line Chen-Lu Wu, Shui-Ping Zhao* and Bi-Lian Yu* Wu et al. Lipids in Health and Disease 2013, 12:186 http://www.lipidworld.com/content/12/1/186 RESEARCH Open Access Microarray analysis provides new insights into the function of apolipoprotein O in HepG2 cell line Chen-Lu Wu, Shui-Ping Zhao* and Bi-Lian Yu* Abstract Background: Apolipoprotein O (apoO) is a new member of the apolipoprotein family. However, data on its physiological functions are limited and inconsistent. Using a microarray expression analysis, this study explored the function of apoO in liver cells. Methods: HepG2 cells were treated either with oleic acid or tumor necrosis factor-α for 24 h. mRNA and protein expression of apoO were assessed by quantitative real-time PCR (qRT-PCR) and Western blot respectively. An efficient lentiviral siRNA vector targeting the human apoO gene was designed and constructed. The gene expression profile of HepG2 human hepatocellular carcinoma cells transfected with the apoO silencing vector was investigated using a whole-genome oligonucleotide microarray. The expression levels of some altered genes were validated using qRT-PCR. Results: ApoO expression in HepG2 cells was dramatically affected by lipid and inflammatory stimuli. A total of 282 differentially expressed genes in apoO-silenced HepG2 cells were identified by microarray analysis. These genes included those participating in fatty acid metabolism, such as ACSL4, RGS16, CROT and CYP4F11, and genes participating in the inflammatory response, such as NFKBIZ, TNFSF15, USP2, IL-17, CCL23, NOTCH2, APH-1B and N2N. The gene Uncoupling protein 2 (UCP2), which is involved in both these metabolic pathways, demonstrated significant changes in mRNA level after transfection. Conclusions: It is likely that apoO participates in fatty acid metabolism and the inflammatory response in HepG2 cells, and UCP2 may act as a mediator between lipid metabolism and inflammation in apoO-silenced HepG2 cells. Keywords: Apolipoprotein O, Inflammation, Lipid metabolism, Fatty acids Background Here, the effects of lipid and inflammatory stimuli on Apolipoprotein O (apoO) is a novel apolipoprotein apoO were investigated. A microarray assay was used to which was first discovered in 2006 [1], but to date, rela- identify genes that are differentially expressed in apoO- tively little is known about its physiological functions. silenced HepG2 cells. This study could enable the func- An in vitro study displayed that purified recombinant tion of apoO in liver cells to be elucidated. apoO facilitated cholesterol efflux from J774 mouse macrophage cells [1]. However, this effect has not been replicated in vivo [2]. Recently, we found that apoO Results levels were increased in acute coronary syndrome pa- Oleic acid increased the expression of apoO in HepG2 tients and positively associated with the inflammatory cells marker high-sensitive C-reactive protein (hsCRP), sug- We determined if a lipid stimulus would influence the ex- gesting a potential role as an inflammatory predictor [3]. pression of apoO in HepG2 cells. Figure 1 shows apoO Therefore, apoO seems to be implicated in lipid metab- mRNA and protein levels in cells treated with oleic acid olism and inflammation. (OA) compared with the levels in control cells. As ex- pected, incubation of HepG2 cells with 1 mmol/L OA for 24 h induced a 4-fold increase in apoO mRNA (P < 0.01) * Correspondence: [email protected]; [email protected] Department of Cardiology, the Second Xiangya Hospital of Central South and a 2-fold increase in apoO protein expression (P < 0.05). University, Middle Ren-Min Road No.139, Changsha, Hunan 410011, PR China © 2013 Wu et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wu et al. Lipids in Health and Disease 2013, 12:186 Page 2 of 10 http://www.lipidworld.com/content/12/1/186 Figure 1 ApoO mRNA and protein changes in HepG2 cells pretreated with 1 mmol/L OA for 24 h. A. The relative levels of apoO mRNA were analyzed by qRT-PCR. Data shown are the mean ± S.E.M from experiments repeated in triplicate with three samples per treatment. **p< 0.01 vs. control. B. The relative levels of apoO protein were analyzed by Western blot analysis. β-actin served as a loading control. These experi- ments were performed three times, and the results of the densitometric analysis and one representative image are shown. * p < 0.05 vs. control. Tumor necrosis factor-α induced the expression of apoO LV2 was identified as an efficient vector capable of in HepG2 cells silencing apoO To explore the effect of inflammatory stimulus on Using GenBank information for the human apoO gene, the expression of apoO, we detected apoO mRNA three interfering sequences and a negative control sequence and protein expression changes in HepG2 cells pre- were designed and designated as LV1, LV2, LV3 and NC. treated for 24 h with 100 ng/mL tumor necrosis PCR identification and DNA sequencing demonstrated the factor-α (TNF-α). Quantitative real-time PCR (qRT- correct insertion of the oligonucleotides into the vectors. PCR) demonstrated that TNF-α treatment led to a qRT-PCR and Western blot analysis confirmed that LV2 3-fold up-regulation of apoO mRNA expression could significantly inhibit apoO expression in HeLa cells (P < 0.01; Figure 2A). ApoO protein levels were ap- when the multiplicity of infection (MOI) =10 (P < 0.001; proximately 2.5-fold higher after incubation (P < 0.05; Figure 3), whereas LV1 and LV3 had no apparent effect Figure 2B). (P > 0.05). Figure 2 Levels of ApoO mRNA and protein in HepG2 cells pretreated with 100 ng/mL TNF-α for 24 h. A. The relative levels of apoO mRNA were analyzed by qRT-PCR. Data shown are the mean ± S.E.M from experiments repeated in triplicate with three samples per treatment. **p < 0.01 vs. control. B. The relative levels of apoO protein were analyzed by Western blot analysis. β-actin served as a loading control. These ex- periments were performed three times, and the results of the densitometric analysis and one representative image are shown. * p < 0.05 vs. control. Wu et al. Lipids in Health and Disease 2013, 12:186 Page 3 of 10 http://www.lipidworld.com/content/12/1/186 Figure 3 Screening for an efficient lentiviral vector capable of silencing apoO expression. A. HeLa cells observed by fluorescence microscopy 3 days after infection (magnification, ×200). B. The relative levels of apoO mRNA transcripts were analyzed by qRT-PCR. Data shown are means ± S.E.M from three independent experiments. **p < 0.001 vs. negative controls (NC). C. Effects of apoO silencing were measured using Western blot. NC: cells infected with negative control RNAi; LV1: cells infected with apoO-specific RNAi-1; LV2: cells infected with apoO-specific RNAi-2; LV3: cells infected with apoO-specific RNAi-3. β-actin served as a loading control. These experiments were performed three times, and the results of the densitometric analysis and one representative image are shown. **p < 0.001 vs. negative control (NC). The LV2 lentiviral vector could dramatically suppress expression patterns, 18 were involved in lipid metabol- apoO expression in HepG2 cells ism (Table 1) and 16 were involved in inflammation Three days after infection, HepG2 cells were visualized (Table 2). Moreover, gene ontology (GO) analysis identi- using fluorescence microscopy. A comparison between fied involvement of the differentially expressed genes in the bright-field and fluorescent images showed that most several cellular biological processes, such as 1) glyceroli- cells had green fluorescent signals when MOI = 20 pid metabolism, 2) glycerophospholipid metabolism, 3) (Figure 4A). The levels of apoO mRNA and protein were sphingolipid catabolism, 4) membrane lipid catabolism, analyzed 5 days and 7 days after transfection, respect- 5) cellular lipid metabolism, 6) phospholipid metabolism, ively. The level of apoO mRNA in cells transfected with 7) phosphatidylinositol metabolism, 8) the Notch signal- apoO-specific-RNAi lentivirus was decreased by ap- ing pathway, 9) steroid catabolism, 10) phospholipid proximately 78% (P < 0.01) compared to the control cells biosynthetic processes, 11) glycerophospholipid biosyn- (Figure 4B). ApoO protein was also down-regulated by thetic processes, 12) sphingolipid metabolism, 13) re- approximately 80% in cells with the apoO-specific RNAi sponse to superoxide, and 14) response to oxygen (P < 0.01; Figure 4C). radicals (Table 3). Differentially expressed genes in apoO-silenced HepG2 Confirmation of microarray results by qRT-PCR cells To validate the microarray results, we assessed the ex- Comparison of mRNA levels between negative control pression of a subset of genes with qRT-PCR, including: cells (NC) and apoO-silenced cells (LV) revealed that NFKBIZ, FBXL21, HRB, NOTCH2, UCP2, ACSL4 and many genes were differentially expressed. In summary, CEL. The high concordance of expression levels found the expression of 282 genes was significantly altered: 192 between the microarray analysis and the qRT-PCR re- genes were up-regulated and 90 genes were down- sults for these genes confirmed that the microarray data regulated (≥2 fold up- or down-regulated; Figure 5A, were reliable (Figure 5B). n = 6, P < 0.05). The expression of the FBXL21 gene, which showed the strongest up-regulation, was increased Discussion by 5.142-fold, whereas the expression of the HRB gene, The liver is the most metabolically active organ in the hu- which showed the strongest down-regulation, was de- man body and is responsible for many vital functions, in- creased by 6.485-fold.
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