P53凋亡刺激蛋白2介导酒精性肝病脂代谢相关基因的转录组学分析

doi:10.3969/j.issn.1006-7795.2023.01.013

首都医科大学学报 ›› 2023, Vol. 44 ›› Issue (1): 85-92.doi: 10.3969/j.issn.1006-7795.2023.01.013

P53凋亡刺激蛋白2介导酒精性肝病脂代谢相关基因的转录组学分析

张莹^1,2, 刘超楠³, 时红林^1,2, 刘芳^1,2, 陈德喜^1,2, 时红波^1,2*

1.首都医科大学附属北京佑安医院北京肝病研究所,北京 100069;
2.北京市肝炎、肝癌精准医学与转化工程技术研究中心,北京 100069;
3.山西中医药大学第三临床学院,山西晋中 030619

收稿日期:2022-05-04 出版日期:2023-02-21 发布日期:2023-01-13
基金资助:
国家重点研发计划(2022YFC2305002),北京市自然科学基金(M22030),北京市医院管理中心“登峰”计划专项经费资助(DFL20221501),北京市属医学科研院所公益发展改革试点项目(京医研2021-10)。

Transcriptome analysis of lipid metabolization-related differential genes mediated by P53 apoptosis-stimulating protein 2 in alcoholic liver disease

Zhang Ying^1,2, Liu Chaonan³, Shi Honglin^1,2, Liu Fang^1,2, Chen Dexi^1,2, Shi Hongbo^1,2*

1. Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China;
2. Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing 100069, China;
3. The Third Clinical College of Shanxi University of Chinese Medicine, Jinzhong 030619, Shanxi Province, China

Received:2022-05-04 Online:2023-02-21 Published:2023-01-13
Contact: *E-mail:shihongbo@ccmu.edu.cn
Supported by:
National Key Research and Development Program of China (2022YFC2305002), Natural Science Foundation of Beijing (M22030), “Peak Climbing” Program of Beijing Hospital Management Center (DFL20221501), Public Welfare Development and Reform Pilot Project of Beijing Municipal Medical Research Institutes (Beijing Medical Research Institute 2021-10).

摘要/Abstract

摘要： 目的应用转录组学测序探讨P53凋亡刺激蛋白2(apoptosis stimulating protein 2,ASPP2)对酒精性肝病脂代谢相关基因表达的影响。方法首先用慢病毒转染人肝细胞HL-7702细胞系,构建7702^{Control-shRNA}和7702^ASPP2-shRNA细胞模型。然后,两组细胞均用400 mmol/L乙醇处理24 h,构建7702^{Control-shRNA}和7702^ASPP2-shRNA酒精肝模型。Illumina测序平台筛选差异表达基因,并进行基因本体(gene ontology,GO)富集分析和互作分析。结果高通量测序以P<0.05且 |log₂(foldchange)|>1的筛选标准获得150个差异表达的基因,其中上调的差异基因有58个,下调92个。其中,与脂代谢相关的上调差异基因有8个,下调差异基因有7个。GO富集分析发现4个脂代谢相关的细胞组分,包括高密度脂蛋白粒子,血浆脂蛋白粒子,脂蛋白粒子以及蛋白－脂质复合物。结论本研究发现15种脂代谢相关差异基因,这些基因可能参与ASPP2介导的酒精性肝病脂代谢,为进一步研究ASPP2在酒精性肝病脂代谢中的调控机制奠定了基础。

关键词: 凋亡刺激蛋白2, 酒精性肝病, 脂代谢, 转录组学, 生物信息学

Abstract: Objective We used the Illumina sequencing platform to investigate the effect of p53 apoptosis stimulating protein 2 (ASPP2) on the expression of genes related to lipid metabolism in alcoholic liver disease. Methods The expression of ASPP2 was down-regulated by human hepatocyte HL-7702 cells infected with lentivirus. The two groups of cells (ASPP2-low and control) were cultured in a definite concentration of alcohol for 24 h. Then we used the Illumina sequencing platform to screen the differentially expressed genes. Then, a functional enrichment analysis and network interaction analysis were performed to explore the biological processes involving these genes. Results Total 150 differentially expressed genes were screened out by high-throughput sequencing according to the criteria of P<0.05 and | log₂ (foldchange) |>1, of which 58 were up-regulated and 92 were down-regulated. Among them, there were 8 up-regulated genes and 7 down-regulated genes related to lipid metabolism. Gene ontology (GO) enrichment analysis found four cell components related to lipid metabolism, including high-density lipoprotein particles, plasma lipoprotein particles, lipoprotein particles, and protein-lipid complexes. Conclusion We found 15 different genes related to lipid metabolism in this study. These genes may be involved in ASPP2 mediated lipid accumulation in alcoholic liver disease, which lays a foundation for further study on the regulation mechanism of ASPP2 in lipid metabolism of alcoholic liver disease.

Key words: apoptosis stimulating protein 2(ASPP2), alcoholic liver disease, lipid metabolism, transcriptomics, bioinformatics

中图分类号:

R64.4
R3

张莹, 刘超楠, 时红林, 刘芳, 陈德喜, 时红波. P53凋亡刺激蛋白2介导酒精性肝病脂代谢相关基因的转录组学分析[J]. 首都医科大学学报, 2023, 44(1): 85-92.

Zhang Ying, Liu Chaonan, Shi Honglin, Liu Fang, Chen Dexi, Shi Hongbo. Transcriptome analysis of lipid metabolization-related differential genes mediated by P53 apoptosis-stimulating protein 2 in alcoholic liver disease[J]. Journal of Capital Medical University, 2023, 44(1): 85-92.

参考文献

[1] Lamas-Paz A, Hao F, Nelson L J, et al. Alcoholic liver disease: utility of animal models [J]. World J Gastroenterol, 2018, 24(45): 5063-5075.
[2] Liu S, Tsai I, Hsu Y. Alcohol-related liver disease: basic mechanisms and clinical perspectives [J]. Int J Mol Sci, 2021, 22(10): 5170.
[3] Kong L, Dong R, Huang K, et al. Yangonin modulates lipid homeostasis, ameliorates cholestasis and cellular senescence in alcoholic liver disease via activating nuclear receptor FXR [J]. Phytomedicine, 2021, 90: 153629.
[4] Israelsen M, Kim M, Suvitaival T, et al. Comprehensive lipidomics reveals phenotypic differences in hepatic lipid turnover in ALD and NAFLD during alcohol intoxication [J]. JHEP Rep, 2021, 3(5): 100325.
[5] Xu P, Yao J, Ji J, et al. Deficiency of apoptosis-stimulating protein 2 of p53 protects mice from acute hepatic injury induced by CCl (4) via autophagy [J]. Toxicol Lett, 2019, 316: 85-93.
[6] Lin M, Chang Y, Xie F, et al. ASPP2 inhibits the profibrotic effects of transforming growth factor-β1 in hepatic stellate cells by reducing autophagy [J]. Dig Dis Sci, 2018, 63(1): 146－154.
[7] Konno T, Kohno T, Okada T, et al. ASPP2 suppression promotes malignancy via LSR and YAP in human endometrial cancer [J]. Histochem Cell Biol, 2020, 154(2): 197-213.
[8] 车阳, 王晋明,王阳,等.P53凋亡刺激蛋白2促进肝细胞脂质蓄积的分子机制研究 [J].北京医学,2022,44(1):49-53.
[9] Yang S, Huang X Y, Zhou N, et al. RNA-Seq analysis of protection against chronic alcohol liver injury by rosa roxburghii fruit juice (Cili) in mice. Nutrients, 2022, 14(9):1974.
[10] Zuo Z, Li Y, Zeng C, et al. Integrated analyses identify key molecules and reveal the potential mechanism of miR-182-5p/FOXO1 axis in alcoholic liver disease [J]. Front Med (Lausanne), 2021, 8: 767584.
[11] Wang S, Sun Y, Wang Y, et al. ASPP2 inhibits hepatitis B virus replication by preventing nucleus translocation of HSF1 and attenuating the transactivation of ATG7 [J]. J Cell Mol Med, 2021, 25(14): 6899-6908.
[12] Martínez-Barquero V, De Marco G, Martínez-Hervas S, et al. Polymorphisms in endothelin system genes, arsenic levels and obesity risk [J]. PLoS One, 2015, 10(3): e0118471.
[13] Vaittinen M, Kolehmainen M, Rydén M, et al. MFAP5 is related to obesity-associated adipose tissue and extracellular matrix remodeling and inflammation [J]. Obesity (Silver Spring), 2015, 23(7): 1371－1378.
[14] Kim E J, Kim Y K, Kim S, et al. Adipochemokines induced by ultraviolet irradiation contribute to impaired fat metabolism in subcutaneous fat cells [J]. Br J Dermatol, 2018, 178(2): 492-501.
[15] Nishimura K, Murakami T, Sakurai T, et al. Circulating apolipoprotein L1 is associated with insulin resistance-induced abnormal lipid metabolism[J]. Sci Rep, 2019,9(1):14869.
[16] Chun J, Zhang J Y, Wilkins M S, et al. Recruitment of APOL1 kidney disease risk variants to lipid droplets attenuates cell toxicity [J]. Proc Natl Acad Sci U S A, 2019, 116(9): 3712-3721.
[17] Dille M, Nikolic A, Wahlers N, et al. Long-term adjustment of hepatic lipid metabolism after chronic stress and the role of FGF21 [J]. Biochim Biophys Acta Mol Basis Dis, 2022, 1868(1): 166286.
[18] Wilson P G, Thompson J C, Shridas P, et al. Serum amyloid A is an exchangeable apolipoprotein[J]. Arterioscler Thromb Vasc Biol, 2018,38(8):1890－1900.
[19] Xiao H, Sun X, Lin Z, et al. Gentiopicroside targets PAQR3 to activate the PI3K/AKT signaling pathway and ameliorate disordered glucose and lipid metabolism[J]. Acta Pharm Sin B, 2022, 12(6):2887-2904.
[20] Hao X, Chen W, Amato A, et al. Multiplexed CRISPR/Cas9 editing of the long-chain acyl-CoA synthetase family in the diatom Phaeodactylum tricornutum reveals that mitochondrial ptACSL3 is involved in the synthesis of storage lipids[J]. New Phytol, 2022, 233(4):1797－1812.
[21] Norman J E, Aung H H, Wilson D W, et al. Inhibition of perilipin 2 expression reduces pro-inflammatory gene expression and increases lipid droplet size[J]. Food Funct, 2018, 9(12):6245-6256.
[22] Giménez-Andrés M, Emeršič T, Antoine-Bally S, et al. Exceptional stability of a perilipin on lipid droplets depends on its polar residues, suggesting multimeric assembly [J]. Elife, 2021, 10: e61401.
[23] Han X, Zhu J, Zhang X, et al. Plin4-dependent lipid droplets hamper neuronal mitophagy in the MPTP/p-induced mouse model of Parkinson's disease [J]. Front Neurosci, 2018, 12: 397.
[24] Pettersen IKN, Tusubira D, Ashrafi H, et al. Upregulated PDK4 expression is a sensitive marker of increased fatty acid oxidation [J]. Mitochondrion, 2019, 49: 97－110.
[25] Zhang M, Zhao Y, Li Z, et al. Pyruvate dehydrogenase kinase 4 mediates lipogenesis and contributes to the pathogenesis of nonalcoholic steatohepatitis [J]. Biochem Biophys Res Commun, 2018, 495(1): 582-586.
[26] Schmidt-Heck W, Matz-Soja M, Aleithe S, et al. Fuzzy modeling reveals a dynamic self-sustaining network of the GLI transcription factors controlling important metabolic regulators in adult mouse hepatocytes [J]. Mol Biosyst, 2015, 11(8): 2190-2197.
[27] Matz-Soja M, Rennert C, Schönefeld K, et al. Hedgehog signaling is a potent regulator of liver lipid metabolism and reveals a GLI-code associated with steatosis [J]. Elife, 2016, 5: e13308.
[28] Morzyglod L, Caüzac M, Popineau L, et al. Growth factor receptor binding protein 14 inhibition triggers insulin-induced mouse hepatocyte proliferation and is associated with hepatocellular carcinoma [J]. Hepatology, 2017, 65(4): 1352－1368.
[29] Zhang J, Zhang Y, Sun T, et al. Dietary obesity-induced Egr-1 in adipocytes facilitates energy storage via suppression of FOXC2 [J]. Sci Rep, 2013, 3: 1476.
[30] Derdak Z, Villegas K A, Wands J R. Early growth response-1 transcription factor promotes hepatic fibrosis and steatosis in long-term ethanol-fed Long-Evans rats [J]. Liver Int, 2012, 32(5): 761-770.

P53凋亡刺激蛋白2介导酒精性肝病脂代谢相关基因的转录组学分析

Transcriptome analysis of lipid metabolization-related differential genes mediated by P53 apoptosis-stimulating protein 2 in alcoholic liver disease

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