PNPLA3对肝细胞和肝癌细胞脂质代谢的影响*

doi:10.3969/j.issn.1672-5069.2020.02.038

摘要/Abstract

摘要： PNPLA3基因在人类和哺乳动物体内都有表达,并且在肝癌细胞中也有表达。PNPLA3在人体和小鼠体内突变后可导致肝细胞内甘油三酯的蓄积,肝细胞发生脂肪变性。在人类和大鼠肝癌细胞使突变型PNPLA3过表达,与过表达野生型PNPLA3细胞比,也会导致肝癌细胞脂质的聚集。本文将归纳总结以往关于PNPLA3基因对肝细胞和肝癌细胞脂质代谢的影响,并分别讨论了PNPLA3对人类肝细胞和肝癌细胞、大鼠和小鼠肝细胞及其肝癌细胞的影响。

关键词: PNPLA3, 甘油三酯, 肝细胞, 肝癌细胞

Abstract: The PNPLA3 gene is expressed in both humans and mammals and is also expressed in liver cancer cells. PNPLA3 can cause accumulation of triglycerides in hepatocytes and fatty degeneration in hepatocytes after its mutation in humans and mice. Overexpression of mutant PNPLA3 in human and rat liver cancer cells also results in lipid accumulation in liver cancer cells compared to overexpression of its wild-type. In this paper, we summarize the effects of PNPLA3 gene on lipid metabolism in hepatocytes and hepatoma cells, and try to explain the effects of PNPLA3 on human hepatocytes and liver cancer cells, rat, mouse hepatocytes and liver cancer cells.

Key words: PNPLA3, Triglyceride, Hepatocytes, Hepatoma cells

宁宝烁, 李异玲. PNPLA3对肝细胞和肝癌细胞脂质代谢的影响^*[J]. 实用肝脏病杂志, 2020, 23(2): 300-304.

Ning Baoshuo, Li Yiling. Effect of PNPLA3 on lipid metabolism of hepatocytes and hepatocellular carcinoma cells[J]. Journal of Practical Hepatology, 2020, 23(2): 300-304.

参考文献

[1] Cohen JC, Horton JD, Hobbs HH.Human fatty liver disease: Old questions and new insights.Science,2011,332(6037):1519-1523.
[2] Day CP. Non-alcoholic fatty liver disease: a massive problem.Clin Med,2011,11(2):176-178.
[3] Bugianesi E, Moscatiello S,Ciaravella MF, et al. Insulin resistance in nonalcoholic fatty liver disease.Curr Pharm Des,2010,16(17):1941-1951.
[4] Hernaez R. Genetic factors associated with the presence and progression of nonalcoholic fatty liver disease: a narrative review.Gastroenterol Hepatol,2012,35(1):32-41.
[5] Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat Genet, 2008,40(12):1461-1465.
[6] Huang Y, Cohen JC, Hobbs HH. Expression and characterization of a PNPLA3 protein isoform (I148M) associated with Nonalcoholic fatty liver disease.J Biol Chem,2011,286(43):37085-37093.
[7] Kershaw EE, Hamm JK, Verhagen LAW, et al. Adipose triglyceride lipase: Function, regulation by insulin, and comparison with adiponutrin. Diabetes,2006,55(1):148.
[8] Romeo S, Kotronen A. Unravelling the pathogenesis of fatty liver disease: patatin-Iike phospholipase domain-containing 3 protein.Curr Opin Lipidol,2010,21(3):247-252.
[9] Raewhitcombe SM, Kennedy D, Voyles M, et al. Regulation of the promoter region of the human adiponutrin/PNPLA3 gene by glucose and insulin.Biochem Biophys Res Commun,2010,402(4):767-772.
[10] Baulande S, Lasnier F, Lucas M, et al. Adiponutrin, a transmembrane protein corresponding to a novel dietary and obesity linked mRNA specifically expressed in the adipose lineage. J Biol Chem,2001,276(36):33336.
[11] Polson DA, Thompson MP. Adiponutrin mRNA expression in white adipose tissue is rapidly induced by meal-feeding a high-sucrose diet. Biochem Biophys Res Commun,2003,301(2):261-266.
[12] Polson DA, Thompson MP. Macronutrient composition of the diet differentially affects leptin and adiponutrin mRNA expression in response to meal feeding.J Nutr Biochem,2004,15(4):242-246.
[13] Li J, Yu X, Pan W, et al. Gene expression profile of rat adipose tissue at the onset of high fat diet obesity.Am J Physiol Endocrinol Metab,2002,282(6):E1334.
[14] Huang Y, Hobbs HH. A feed forward loop amplifies nutritional regulation of PNPLA3.Proc Natl Acad of Sci U S A,2010,107(17):7892-7897.
[15] Liu Y, Moldes M, Bastard JP, et al. Adiponutrin: A new gene regulated by energy balance in human adipose tissue.J Clin Endocrinol Metab, 2004, 89(6):2684-2689.
[16] Perttilä J, Huamansamanez C, Caron S, et al. PNPLA3 is regulated by glucose in humanhepatocytes, and its I148M mutant slows down triglyceride hydrolysis.Am J Physiol Endocrinol Metab,2012,302(9):E1063.
[17] Soni KG, Mardones GA, Sougrat R, et al. Coatomer-dependent protein delivery to lipid droplets.J Cell Sci,2009,122(11):1834-1841.
[18] He S, Mcphaul C, Li JZ, et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis.J Biol Chem,2010,285(9):6706-6715.
[19] Victor RG, Haley RW, Willett DL, et al. Dallas heart study investigators. The Dallas heart study: a population based probability sample for the multidisciplinary study of ethnic differences in cardiovascular health.Am J Cardiol,2004,93(12):1473-1480.
[20] Speliotes EK, Yergesarmstrong LM, Wu J, et al. Genome wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.Plos Genet,2011,7(3):E1001324.
[21] Luukkonen PK, Zhou Y, Sädevirta S, et al. Hepatic ceramides dissociate steatosis and insulin resistance in patients with nonalcoholic fatty liver disease.J Hepatol,2016,64(5):1167-1175.
[22] Smagris E, Basuray S, Li J, et al. Pnpla3 I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology,2015,61(1):108-118.
[23] Li JZ, Huang Y, Karaman R, et al. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis.J Clin Invest,2012,122(11):4130-4144.
[24] 乔爱君. 小鼠PNPLA3基因影响机体糖脂代谢及FoxO1抑制SREBP-1c表达的分子机制研究.北京协和医学院(中国医学科学院);北京协和医学院;中国医学科学院;清华大学医学部,2011.
[25] Kumashiro N, Yoshimura T, Cantley JL, et al. Role of patatin like phospholipase domain containing 3 on lipid induced hepatic steatosis and insulin resistance in rats.Hepatology,2013,57(5):1763-1772.
[26] Hoekstra M, Li ZJ, Van EM, et al. The expression level of non alcoholic fatty liver disease related gene PNPLA3 in hepatocytes is highly influenced by hepatic lipid status.J Hepatol,2010,52(2):244-251.
[27] Basantani MK, Sitnick MT, Cai L, et al. Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome.J Lipid Res,2011,52(2):318.
[28] Kollerits B, Coassin S, Beckmann ND, et al. Genetic evidence for a role of adiponutrin in the metabolism of apolipoprotein B containing lipoproteins.Hum Mol Genet,2015,18(23):4669-4676.
[29] Lake AC, Sun Y, Li JL, et al. Expression, regulation and triglyceride hydrolase activity of adiponutrin family members.J Lipid Res,2005,46(11):2477.
[30] Jenkins CM, Mancuso DJ, Yan W, et al. Identification, cloning, expression and purification of three novel human calcium independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J Biol Chem,2004,279(47):48968-48975.
[31] Zechner R, Strauss JG, Haemmerle G, et al. Lipolysis: pathway under construction.Curr Opin Lipidol,2005,16(3):333-340.
[32] Goran MI, Walker R, Allayee H. Genetic related and carbohydrate related factors affecting liver fat accumulation.Clin Nutr,2012,15(4):392.
[33] Davis JN, Lê KA, Walker RW, et al. Increased hepatic fat in overweight hispanic youth influenced by interaction between genetic variation in PNPLA3 and high dietary carbohydrate and sugar consumption.Am.J Clin Nutr,2010,92(6):1522-1527.
[34] Valenti L, Al-Serri A, Daly AK, et al. Homozygosity for the patatin like phospholipase 3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology,2010,51(4):1209-1217.
[35] Taskinen MR, Adiels M, Westerbacka J, et al. Dual metabolic defects are required to produce hypertriglyceridemia in obese subjects. Atherosclerosis,2011,12(1):13.
[36] Chan DC, Watts GF, Gan SK, et al. Nonalcoholic fatty liver disease as the transducer of hepatic oversecretion of very low density lipoprotein apolipoprotein B100 in obesity.Arterioscler.Thromb Vasc Biol,2010,30(5):1043.
[37] Pirazzi C, Adiels M, Burza MA, et al. Patatin like phospholipase domain containing 3 ( PNPLA3 ) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro.J Hepatol,2012,57(6):1276-1282.
[38] Kumari, Manju, Schoiswohl, et al. Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase.Cell Metab,2012,15(5):691-702.
[39] Dubuquoy C, Robichon C, Lasnier F, et al. Distinct regulation of adiponutrin/PNPLA3 gene expression by the transcription factors ChREBP and SREBP1c in mouse and human hepatocytes.J Hepatol,2011,55(1):145-153.
[40] Ruhanen H, Perttilä J, Hölttä-Vuori M, et al. PNPLA3 mediates hepatocyte triacylglycerol remodeling.J Lipid Res,2014,55(4):739-746.
[41] Green CJ, Johnson D, Amin HD, et al. Characterization of lipid metabolism in a novel immortalized human hepatocyte cell line.Am J Physiol Endocrinol Metab,2015,309(6):E511-E522.
[42] Pirazzi C, Adiels M, Burza MA, et al. Patatin like phospholipase domain containing 3 ( PNPLA3 ) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J Hepatol,2012,57(6):1276-1282.
[43] Li JZ, Huang Y, Karaman R, et al. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis.J Clin Invest,2012,122(11):4130-4144.
[44] Smagris E, Basuray S, Li J, et al. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis.Hepatology,2015,61(1):108-118.
[45] Hao L, Ito K, Huang KH, et al. Shifts in dietary carbohydrate lipid exposure regulate expression of the nonalcoholic fatty liver disease associated gene PNPLA3/adiponutrin in mouse liver and HepG2 human liver cells.Metabolism,2014,63(10):1352-1362.
[46] Kershaw EE, Hamm JK, Verhagen LAW, et al. Adipose triglyceride lipase: function, regulation by insulin, and comparison with adiponutrin.Diabetes,2006,55(1):148.

PNPLA3对肝细胞和肝癌细胞脂质代谢的影响^*

Effect of PNPLA3 on lipid metabolism of hepatocytes and hepatocellular carcinoma cells

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

[1]	任国亮, 李连生, 刘刚, 丰帆, 刘婧. 热量限制饮食对非酒精性脂肪性肝病患者胰岛素抵抗、血脂和氧化应激指标的影响^*[J]. 实用肝脏病杂志, 2020, 23(2): 219-222.
[2]	王玮, 杜晓菲, 路运健. 术前NLR水平对TACE联合MWA治疗的巨块型原发性肝癌患者生存时间的影响^*[J]. 实用肝脏病杂志, 2020, 23(2): 260-263.
[3]	李天纵, 周松, 周石. 肝细胞癌患者TACE治疗前后血清miR-145水平变化及其临床意义[J]. 实用肝脏病杂志, 2020, 23(2): 264-267.
[4]	胡鸿, 廖运国, 魏欣, 唐梓瑜, 邓丹, 蒲嘉骐, 钟立明. ¹²⁵I粒子植入或3DCRT联合TACE治疗晚期原发性肝癌患者临床疗效对比研究^*[J]. 实用肝脏病杂志, 2020, 23(2): 268-271.
[5]	刘潇, 何年安, 叶显俊, 刘力, 付文学, 陈姣姣. 超声造影对肝细胞癌与肝转移癌的鉴别诊断价值分析[J]. 实用肝脏病杂志, 2020, 23(1): 94-97.
[6]	石莹莹, 王元喜. 应用肝脏影像报告与数据管理系统诊断肝细胞癌的价值研究^*[J]. 实用肝脏病杂志, 2020, 23(1): 98-101.
[7]	马宁, 戴晓雯, 吴建江. 肝部分切除术患者目标导向性液体治疗疗效及安全性研究^*[J]. 实用肝脏病杂志, 2020, 23(1): 102-105.
[8]	高莉, 高屹, 尹秋萍. CT灌注成像联合彩色多普勒超声造影辨别肝脏结节性病变性质临床价值探讨^*[J]. 实用肝脏病杂志, 2020, 23(1): 106-109.
[9]	胡利琳, 王玮珺, 杨玲. 肝细胞型胆汁淤积诊治进展[J]. 实用肝脏病杂志, 2020, 23(1): 156-160.
[10]	曹策, 郁义星, 王贝贝, 赵卫峰. 增强磁共振成像联合血清甲胎蛋白和脱-γ-羧基凝血酶原诊断肝细胞癌临床价值探讨[J]. 实用肝脏病杂志, 2019, 22(6): 896-899.
[11]	廖桂婵, 彭颉, 张小勇. 肝细胞介导的天然免疫应答参与控制乙型肝炎病毒感染^*[J]. 实用肝脏病杂志, 2019, 22(5): 617-619.
[12]	朱俊, 丁莹, 王世清, 张野, 刘野, 刘泽刚. 围手术期应用乌司他丁治疗对肝细胞癌患者肝切除术后外周血Th22细胞百分比和血浆白细胞介素-22的影响*[J]. 实用肝脏病杂志, 2019, 22(5): 720-723.
[13]	王刚, 赵洪波, 朱亚玲, 蒋保三, 张越美, 刁勇. 基于数据库分析肝细胞癌细胞XPO5基因水平变化及其临床意义*[J]. 实用肝脏病杂志, 2019, 22(5): 724-727.
[14]	戴青云, 王润东, 荚卫东. 术前预后营养指数评估肝细胞癌患者肝切除术后早期肿瘤复发价值探讨^*[J]. 实用肝脏病杂志, 2019, 22(4): 561-564.
[15]	杨富存, 尚怀学, 盖永浩. 钆塞酸二钠增强磁共振扫描诊断肝脏局灶性病变研究^*[J]. 实用肝脏病杂志, 2019, 22(4): 577-580.