肝细胞核因子4α在肝脏疾病发生发展中的作用

杨金连; 汪艳

doi:10.3969/j.issn.1001-5256.2016.02.045

肝细胞核因子4α在肝脏疾病发生发展中的作用

DOI: 10.3969/j.issn.1001-5256.2016.02.045

杨金连,
汪艳

1. 南方医科大学南方医院感染内科器官衰竭防治国家重点实验室广东省病毒性肝炎研究重点实验室
2. 南方医科大学药学院

基金项目:

国家自然科学基金(3110701);国家自然科学基金(81371603)；广东省科技计划项目(2013B051000051)；

详细信息

中图分类号: R575
计量
- 文章访问数: 1399
- HTML全文浏览量: 76
- PDF下载量: 414
- 被引次数: 0
出版历程
- 收稿日期: 2015-06-24
- 出版日期: 2016-02-20

The role of hepatocyte nuclear factor 4 alpha in development and progression of liver diseases

Department of Infectious Diseases,State Key Laboratory of Organ Failure Research,Guangdong Provincial Key Laboratory of Viral Hepatitis Research,Nanfang Hospital of Southern Medical University

Research funding:

摘要

摘要: 肝细胞核因子(HNF)4α属于细胞核受体超家族成员,在分化成熟的肝细胞中高表达。HNF4α在转录水平上调控肝脏特异基因的表达,促进肝细胞的发育和分化,参与肝细胞极性的建立和维持,增强肝脏的合成、代谢以及解毒功能。HNF4α可通过抑制肝星状细胞的活化、逆转上皮间质细胞转化、抑制肝癌细胞增殖、侵袭和转移等机制,参与肝纤维化、肝硬化、肝细胞癌等疾病的发生和变化过程。阐述了HNF4α的生物学功能,对其参与多种主要肝脏疾病信号通路机制的研究进展进行了分析总结,旨在为进一步发掘这一潜在的肝脏疾病靶向治疗途径提供参考。
- 肝疾病 /
- 肝细胞核因子4 /
- 综述
Abstract: Hepatocyte nuclear factor 4 alpha( HNF4α),a member of the nuclear receptor superfamily,has a high expression level in mature hepatocytes. HNF4α can regulate hepatocyte- specific gene expression at a transcriptional level,promote hepatocyte development and differentiation,participate in establishment and maintenance of hepatocyte polarity,and enhance the synthetic,metabolic,and detoxifying functions of the liver. Through inhibiting the activation of hepatic stellate cells,reversing epithelial- mesenchymal transition,and inhibiting the proliferation,invasion,and metastasis of hepatoma cells,HNF4α may be involved in the development and progression of various liver diseases including liver fibrosis,liver cirrhosis,and hepatocellular carcinoma. This paper elaborates on the biological functions of HNF4α,and summarizes and analyzes the research advances in the mechanisms of action of HNF4α in the pathological process of liver diseases,in order to provide references for further investigation of the potential targeted therapies for liver diseases.
- liver diseases /
- hepatocyte nuclear factor 4 /
- review

HTML全文

参考文献(69)

[1]TANAKA T,JIANG S,HOTTA H,et al.Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4αin the pathogenesis of human cancer[J].J Pathol,2006,208(5):662-672.

[2]WATT AJ,GARRISON WD,DUNCAN SA.HNF4:A central regulator of hepatocyte differentiation and function[J].Hepatology,2003,37(6):1249-1253.

[3]LI J,NING G,DUNCAN SA.Mammalian hepatocyte differentiation requires the transcription factor HNF-4α[J].Gene Dev,2000,14(4):464-474.

[4]WANG YP,HE Q,WU F,et al.Effects of Wnt3a on proliferation,activation and the expression of TGFβ/Smad in rat hepatic stellate cells[J].Chin J Hepatol,2013,21(2):111-115.(in Chinese)王燕平,贺琪,吴飞,等.Wnt3a对肝星状细胞增殖活化以及转化生长因子β/Smad表达的影响[J].中华肝脏病杂志,2013,21(2):111-115.

[5]FAN TT,HU PF,WANG J,et al.Regression effect of hepatocyte nuclear factor 4αon liver cirrhosis in rats[J].J Dig Dis,2013,14(6):318-327.

[6]KRITIS AA,ARGYROKASTRITIS A,MOSCHONAS NK,et al.Isolation and characterization of a third isoform of human hepatocyte nuclear factor 4[J].Gene,1996,173(2):275-280.

[7]SCHREM H,KLEMPNAUER J,BORLAK J.Liver-enriched transcription factors in liver function and development.PartⅡ:the C/EBPs and D site-binding protein in cell cycle control,carcinogenesis,circadian gene regulation,liver regeneration,apoptosis,and liver-specific gene regulation[J].Pharmacol Rev,2004,56(2):291-330.

[8]SLADEK FM,ZHONG WM,LAI E,et al.Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily[J].Genes Dev,1990,4(12B):2353-2365.

[9]HERTZ R,KALDERON B,BYK T,et al.Thioesterase activity and acyl-CoA/fatty acid cross-talk of hepatocyte nuclear factor-4α[J].J Biol Chem,2005,280(26):24451-24461.

[10]DREWES T,SENKEL S,HOLEWA B,et al.Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes[J].Mol Cell Biol,1996,16(3):925-931.

[11]NAKHEI H,LINGOTT A,LEMM I,et al.An alternative splice variant of the tissue specific transcription factor HNF4alpha predominates in undifferentiated murine cell types[J].Nucleic Acids Res,1998,26(2):497-504.

[12]JOVER R,BORT R,GMEZ-LECHN MJ,et al.Cytochrome P450 regulation by hepatocyte nuclear factor 4 in human hepatocytes:a study using adenovirus-mediated antisense targeting[J].Hepatology,2001,33(3):668-675.

[13]CHOU WC,PROKOVA V,SHIRAISHI K,et al.Mechanism of a transcriptional cross talk between transforming growth factor-betaregulated Smad3 and Smad4 proteins and orphan nuclear receptor hepatocyte nuclear factor-4[J].Mol Biol Cell,2003,14(3):1279-1294.

[14]ODOM DT,ZIZLSPERGER N,GORDON DB,et al.Control of pancreas and liver gene expression by HNF transcription factors[J].Science,2004,303(5662):1378-1381.

[15]LU H,GONZALEZ FJ,KLAASSEN C.Alterations in hepatic mRNA expression of phase II enzymes and xenobiotic transporters after targeted disruption of hepatocyte nuclear factor 4 alpha[J].Toxicol Sci,2010,118(2):380-390.

[16]BONZO JA,FERRY CH,MATSUBARA T,et al.Suppression of hepatocyte proliferation by hepatocyte nuclear factor 4 in adult mice[J].J Biol Chem,2012,287(10):7345-7356.

[17]BATTLE MA,KONOPKA G,PARVIZ F,et al.Hepatocyte nuclear factor 4alpha orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver[J].Proc Natl Acad Sci U S A,2006,103(22):8419-8424.

[18]NAGY P,BISGAARD HC,THORGEIRSSON SS.Expression of hepatic transcription factors during liver development and oval cell differentiation[J].J Cell Biol,1994,126(1):223-233.

[19]PARVIZ F,MATULLO C,GARRISON WD,et al.Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis[J].Nat Genet,2003,34(3):292-296.

[20]ZHANG Q,LEI X,LU H.Alterations of epigenetic signatures in hepatocyte nuclear factor 4αdeficient mouse liver determined by improved Ch IP-q PCR and(h)MeD IP-q PCR assays[J].PLoS One,2014,9(1):e84925.

[21]YIN L,MA H,GE X,et al.Hepatic hepatocyte nuclear factor 4 is essential for maintaining triglyceride and cholesterol homeostasis[J].Arterioscler Thromb Vasc Biol,2011,31(2):328-336.

[22]WALESKY C,EDWARDS G,BORUDE P,et al.Hepatocyte nuclear factor 4 alpha deletion promotes diethylnitrosamine-induced hepatocellular carcinoma in rodents[J].Hepatology,2013,57(6):2480-2490.

[23]GUAN M,QU L,TAN W,et al.Hepatocyte nuclear factor-4 alpha regulates liver triglyceride metabolism in part through secreted phospholipase A2 GXIIB[J].Hepatology,2011,53(2):458-466.

[24]PRAMFALK C,KARLSSON E,GROOP L,et al.Control of ACAT2 liver expression by HNF4:lesson from MODY1 patients[J].Arterioscler Thromb Vasc Biol,2009,29(8):1235-1241.

[25]OHOKA N,OKUHIRA K,CUI H,et al.HNF4αincreases liverspecific human ATP-binding cassette transporter A1 expression and cholesterol efflux to apolipoprotein A-I in response to cholesterol depletion[J].Arterioscler Thromb Vasc Biol,2012,32(4):1005-1014.

[26]HWANG-VERSLUES WW,SLADEK FM.HNF4α-role in drug metabolism and potential drug target?[J].Curr Opin Pharmacol,2010,10(6):698-705.

[27]GUENGERICH FP.Cytochrome P-450 3A4:regulation and role in drug metabolism[J].Annu Rev Pharmacol,1999,39(1):1-17.

[28]TIRONA RG,LEE W,LEAKE BF,et al.The orphan nuclear receptor HNF4αdetermines PXR-and CAR-mediated xenobiotic induction of CYP3A4[J].Nat Med,2003,9(2):220-224.

[29]ECHCHGADDA I,SONG CS,OH T,et al.The xenobiotic-sensing nuclear receptors pregnane X receptor,constitutive androstane receptor,and orphan nuclear receptor hepatocyte nuclear factor4alpha in the regulation of human steroid-/bile acid-sulfotransferase[J].Mol Endocrinol,2007,21(9):2099-2111.

[30]KAMIYAMA Y,MATSUBARA T,YOSHINARI K,et al.Role of human hepatocyte nuclear factor 4alpha in the expression of drug-metabolizing enzymes and transporters in human hepatocytes assessed by use of small interfering RNA[J].Drug Metab Pharmacokinet,2007,22(4):287-298.

[31]CHIBA H,SAKAI N,MURATA M,et al.The nuclear receptor hepatocyte nuclear factor 4 acts as a morphogen to induce the formation of microvilli[J].J Cell Biol,2006,175(6):971-980.

[32]WANG Y,TOH YC,LI Q,et al.Mechanical compaction directly modulates the dynamics of bile canaliculi formation[J].Integr Biol(Camb),2013,5(2):390-401.

[33]HAYHURST GP,STRICK-MARCHAND H,MULET C,et al.Morphogenetic competence of HNF4α-deficient mouse hepatic cells[J].J Hepatol,2008,49(3):384-395.

[34]FRIEDMAN SL.Liver fibrosis-from bench to bedside[J].J Hepatol,2003,38(Suppl 1):s38-s53.

[35]FAUSTHER M,LAVOIE EG,DRANOFF JA.Contribution of myofibroblasts of different origins to liver fibrosis[J].Curr Pathobiol Rep,2013,1(3):225-230.

[36]ZEISBERG M,YANG C,MARTINO M,et al.Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition[J].J Biol Chem,2007,282(32):23337-23347.

[37]OMENETTI A,PORRELLO A,JUNG Y,et al.Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans[J].J Clin Invest,2008,118(10):3331-3342.

[38]WU F,HUANG S,ZHU N,et al.Recombinant human histidine triad nucleotide-binding protein 1 attenuates liver fibrosis induced by carbon tetrachloride in rats[J].Mol Med Rep,2013,8(4):1023-1028.

[39]ZHU NL,WANG J,TSUKAMOTO H.The necdin-wnt pathway causes epigenetic peroxisome proliferator-activated receptor repression in hepatic stellate cells[J].J Biol Chem,2010,285(40):30463-30471.

[40]ARELLANES-ROBLEDO J,REYES-GORDILLO K,SHAH R,et al.Fibrogenic actions of acetaldehyde areβ-catenin dependent but Wingless independent:a critical role of nucleoredoxin and reactive oxygen species in human hepatic stellate cells[J].Free Radical Bio Med,2013,65:1487-1496.

[41]YUE HY,YIN C,HOU JL,et al.Hepatocyte nuclear factor 4 attenuates hepatic fibrosis in rats[J].Gut,2010,59(2):236-246.

[42]ZHONG W,SHEN W,NING B,et al.Inhibition of extracellular signal-regulated kinase 1 by adenovirus mediated small interfering RNA attenuates hepatic fibrosis in rats[J].Hepatology,2009,50(5):1524-1536.

[43]ZHAO J,TANG N,WU K,et al.MiR-21 simultaneously regulates ERK1 signaling in HSC activation and hepatocyte EMT in hepatic fibrosis[J].PLoS One,2014,9(10):e108005.

[44]ZHANG Y,BONZO JA,GONZALEZ FJ,et al.Diurnal regulation of the early growth response 1(Egr-1)protein expression by hepatocyte nuclear factor 4(HNF4)and small heterodimer partner(SHP)cross-talk in liver fibrosis[J].J Biol Chem,2011,286(34):29635-29643.

[45]Ministry of Health of the People's Republic of China.Diagnosis,management,and treatment of hepatocellular carcinoma(V2011)[J].J Clin Hepatol,2011,27(11):1141-1159.(in Chinese)中华人民共和国卫生部.原发性肝癌诊疗规范(2011年版)[J].临床肝胆病杂志,2011,27(11):1141-1159.

[46]LAZAREVICH NL,CHEREMNOVA OA,VARGA EV,et al.Progression of HCC in mice is associated with a downregulation in the expression of hepatocyte nuclear factors[J].Hepatology,2004,39(4):1038-1047.

[47]YIN C,LIN Y,ZHANG X,et al.Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4αgene[J].Hepatology,2008,48(5):1528-1539.

[48]YAO D,PENG S,DAI C.The role of hepatocyte nuclear factor4alpha in metastatic tumor formation of hepatocellular carcinoma and its close relationship with the mesenchymal-epithelial transition markers[J].BMC Cancer,2013,13:432.

[49]CHUA HL,BHAT-NAKSHATRI P,CLARE SE,et al.NF-κB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells:potential involvement of ZEB-1 and ZEB-2[J].Oncogene,2007,26(5):711-724.

[50]WU Y,DENG J,RYCHAHOU PG,et al.Stabilization of snail by NF-κB is required for inflammation-induced cell migration and invasion[J].Cancer Cell,2009,15(5):416-428.

[51]CICCHINI C,FILIPPINI D,COEN S,et al.Snail controls differentiation of hepatocytes by repressing HNF4αexpression[J].J Cell Physiol,2006,209(1):230-238.

[52]NING B,DING J,LIU J,et al.Hepatocyte nuclear factor 4α-nuclear factor-κB feedback circuit modulates liver cancer progression[J].Hepatology,2014,60(5):1607-1619.

[53]AVALLE L,PENSA S,REGIS G,et al.STAT1 and STAT3 in tumorigenesis[J].JAKSTAT,2014,1(2):65-72.

[54]WANG X,CROWE PJ,GOLDSTEIN D,et al.STAT3 inhibition,a novel approach to enhancing targeted therapy in human cancers(review)[J].Int J Oncol,2012,41(4):1181-1191.

[55]ZHANG C,XU G,JIA W,et al.Activation of STAT3 signal pathway correlates with twist and E-cadherin expression in hepatocellular carcinoma and their clinical significance[J].J Surg Res,2012,174(1):120-129.

[56]HATZIAPOSTOLOU M,POLYTARCHOU C,AGGELIDOU E,et al.An HNF4α-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis[J].Cell,2011,147(6):1233-1247.

[57]YANG M,LI SN,ANJUM KM,et al.A double-negative feedback loop between Wnt-catenin signaling and HNF4 regulates epithelial-mesenchymal transition in hepatocellular carcinoma[J].J Cell Sci,2013,126(24):5692-5703.

[58]NING BF,DING J,YIN C,et al.Hepatocyte nuclear factor 4 alpha suppresses the development of hepatocellular carcinoma[J].Cancer Res,2010,70(19):7640-7651.

[59]WU Q,LIU H,LIU Y,et al.Decreased expression of hepatocyte nuclear factor 4α(Hnf4α)/microRNA-122(miR-122)axis in hepatitis B virus-associated hepatocellular carcinoma enhances potential oncogenic GALNT10 protein activity[J].J Biol Chem,2015,290(2):1170-1185.

[60]YIN C,WANG P,XU W,et al.Hepatocyte nuclear factor-4αreverses malignancy of hepatocellular carcinoma through regulating miR-134 in the DLK1-DIO3 region[J].Hepatology,2013,58(6):1964-1976.

[61]LI X,JIANG H,QU L,et al.Hepatocyte nuclear factor 4αand downstream secreted phospholipase A2 GXIIB regulate production of infectious hepatitis C virus[J].J Virol,2013,88(1):612-627.

[62]QUASDORFF M,HOSEL M,ODENTHAL M,et al.A concerted action of HNF4αand HNF1αlinks hepatitis B virus replication to hepatocyte differentiation[J].Cell Microbiol,2008,10(7):1478-1490.

[63]HE F,CHEN EQ,LIU L,et al.Inhibition of hepatitis B virus replication by hepatocyte nuclear factor 4-alpha specific short hairpin RNA[J].Liver Int,2012,32(5):742-751.

[64]CHEN EQ,SUN H,FENG P,et al.Study of the expression levels of Hepatocyte nuclear factor 4 alpha and 3 beta in patients with different outcome of HBV infection[J].Virol J,2012,9:23.

[65]YU X,MERTZ JE.Distinct modes of regulation of transcription of hepatitis B virus by the nuclear receptors HNF4alpha and COUPTF1[J].J Virol,2003,77(4):2489-2499.

[66]YAMAZAKI T,SHIRAISHI S,KISHIMOTO K,et al.An increase in liver PPARγ2 is an initial event to induce fatty liver in response to a diet high in butter:PPARγ2 knockdown improves fatty liver induced by high-saturated fat[J].J Nutr Biochem,2011,22(6):543-553.

[67]PARK YJ,KIM SC,KIM J,et al.Dissociation of diabetes and obesity in mice lacking orphan nuclear receptor small heterodimer partner[J].J Lipid Res,2011,52(12):2234-2244.

[68]KIM SC,KIM C,AXE D,et al.All-trans-retinoic acid ameliorates hepatic steatosis in mice by a novel transcriptional cascade[J].Hepatology,2014,59(5):1750-1760.

[69]MARTINEZ-JIMENEZ CP,KYRMIZI I,CARDOT P,et al.Hepatocyte nuclear factor 4alpha coordinates a transcription factor network regulating hepatic fatty acid metabolism[J].Mol Cell Biol,2010,30(3):565-577.

施引文献

资源附件(0)

访问统计