肝星状细胞激活的内在机制
张锦生,复旦大学上海医学院病理学系 上海市 200032
张锦生,男, 1944-3-14生, 江苏省镇江市人, 汉族. 1968年原上海第一医学院医学系毕业, 1985年原上海医科大学博士学位. 教授, 博士生导师, 主要从事肝病病理研究.
国家自然科学基金资助项目, No. 39970337, N0. 30170417
通讯作者:张锦生, 200032, 上海市医学院路138号, 复旦大学上海医学院病理学系. jszhang44@shmu.edu.cn
电话: 021-54237049 传真: 021-54237539
, 百拇医药
收稿日期: 2004-12-27 接受日期: 2005-03-02
摘要激活的肝星状细胞是肝纤维化时产生细胞外基质的主要细胞.细胞因子的旁分泌和自分泌作用、氧化应激、微环境ECM的改变是激活肝星状细胞的主要外部机制，激活时最初的显著变化是细胞质内脂滴和维生素A减少甚至消失，并表达a-平滑肌肌动蛋白.脂滴(含中性脂肪)的存在意味着向脂肪细胞分化，肝星状细胞向脂肪细胞分化及去分化与其激活有何关联，是激活时重要的分子机制之一，还是仅仅为一种伴随现象？最近的工作表明，与脂肪细胞分化密切相关的C/EBP-a和PPARg基因表达下调及维生素A信号转导削弱是肝星状细胞激活的重要内在机制.如果能从肝星状细胞激活的外部和内在机制两方面都进行干预的话，有可能提高肝纤维化的疗效.
关键词:肝星状细胞; 肝纤维化;激活
张锦生. 肝星状细胞激活的内在机制. 世界华人消化杂志 2005;13(7):831-8341 Friedman SL. Liver fibrosis-from bench to bedside. J Hepatol 2003;38(Suppl 1):S38-53
, 百拇医药
2 Friedman SL. Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis.
Mechanisms and treatment strategies. N Engl J Med 1993;328:1828-1835
3 Lee KS, Buck M, Houglum K, Chojkier M. Activation of hepatic stellate cells by TGF alpha and collagen type I is mediated
by oxidative stress through c-myb expression. J Clin Invest 1995;96:2461-2468
, 百拇医药
4 Friedman SL, Roll FJ, Boyles J, Arenson DM, Bissell DM. Maintenance of differentiated phenotype of cultured rat hepatic
lipocytes by basement membrane matrix. J Biol Chem 1989;264:10756-10762
5 Meyer DH, Krull N, Dreher KL, Gressner AM. Biglycan and decorin gene expression in normal and fibrotic rat liver:cellular
localization and regulatory factors. Hepatology 1992;16:204-216
, 百拇医药
6 Roskams T, Moshage H, De Vos R, Guido D, Yap P, Desmet V. Heparan sulfate proteoglycan expression in normal
human liver. Hepatology 1995;21:950-958
7 Musso O, Rehn M, Saarela J, Theret N, Lietard J, Hintikka, Lotrian D, Campion JP, Pihlajaniemi T, Clement B. Collagen
XVIII is localized in sinusoids and basement membrane zones and expressed by hepatocytes and activated stellate cells
, 百拇医药
in fibrotic human liver. Hepatology 1998;28:98-107
8 Geerts A. History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells.
Semin Liver Dis 2001;21:311-335
9 Yokoi Y, Namihisa T, Kuroda H, Komatsu I, Miyazaki A, Watanabe S, Usui K. Immunocytochemical detection of desmin
in fat-storing cells(Ito cells). Hepatology 1984;4:709-714
, 百拇医药
10 Gard AL, White FP, Dutton GR. Extra-neural glial fibrillary acidic protein(GFAP)immunoreactivity in perisinusoidal
stellate cells of rat liver. J Neuroimmunol 1985;8:359-375
11 Ramadori G, Veit T, Schwogler S, Dienes HP, Knittel T, Rieder H, Meyer zum Buschenfelde KH. Expression of the gene
of the alpha-smooth muscle-actin isoform in rat liver and in rat fat-storing(ITO)cells.
, 百拇医药
Virchows Arch B Cell Pathol Incl Mol Pathol 1990;59:349-357
12 Enzan H, Himeno H, Iwamura S, Saibara T, Onishi S, Yamamoto Y, Hara H. Immunohistochemical identification of Ito
cells and their myofibroblastic transformation in adult human liver. Virchows Arch 1994;424:249-256
13 Suskind DL, Muench MO. Searching for common stem cells of the hepatic and hematopoietic systems in the human
, http://www.100md.com
fetal liver:CD34+ cytokeratin 7/8+ cells express markers for stellate cells. J Hepatol 2004;40:261-268
14 Cassiman D, van Pelt J, De Vos R, Van Lommel F, Desmet V, Yap SH, Roskams T. Synaptophysin:A novel marker
for human and rat hepatic stellate cells. Am J Pathol 1999;155:1831-1839
15 Cassiman D, Denef C, Desmet VJ, Roskams T. Human and rat hepatic stellate cells express neurotrophins and
, 百拇医药
neurotrophin receptors. Hepatology 2001;33:148-158
16 Trim N, Morgan S, Evans M, Issa R, Fine D, Afford S, Wilkins B, Iredale J. Hepatic stellate cells express the low
affinity nerve growth factor receptor p75 and undergo apoptosis in response to nerve growth factor stimulation.
Am J Pathol 2000;156:1235-1243
17 Johnson PF, Landschulz WH, Graves BJ, McKnight SL. Identification of a rat liver nuclear protein that binds to the
, 百拇医药
enhancer core element of three animal viruses. Genes Dev 1987;1:133-146
18 黄光存, 张锦生.CCAAT/增强子结合蛋白家族与肝脏疾病.中华肝脏病杂志 2003;11:57-59
19 Tang QQ, Jiang MS, Lane MD. Repressive effect of Sp1 on the C/EBPalpha gene promoter:role in adipocyte
differentiation. Mol Cell Biol 1999;19:4855-4865
20 Huang GC, Zhang JS, Tang QQ. Involvement of C/EBP-alpha gene in in vitro activation of rat hepatic stellate cells.
, 百拇医药
Biochem Biophys Res Commun 2004;324:1309-1318
21 Huang J, Zhang JS, Huang GC, Tang QQ, Chen C, Zhang XR, Chen Q. Expression of CCAAT/enhancer-binding protein
in cultured rat hepatic stellate cells and its significance. Zhonghua Ganzangbing Zazhi 2004;12:259-262
22 Takiguchi M. The C/EBP family of transcription factors in the liver and other organs. Int J Exp Pathol 1998;79:369-391
, 百拇医药
23 Vanden Heuvel JP. Peroxisome proliferator-activated receptors:a critical link among fatty acids, gene expression and
carcinogenesis. J Nutr 1999;129(2S Suppl):575S-580S
24 Galli A, Crabb D, Price D, Ceni E, Salzano R, Surrenti C, Casini A. Peroxisome proliferator-activated receptor gamma
transcriptional regulation is involved in platelet-derived growth factor-induced proliferation of human hepatic stellate
, 百拇医药
cells. Hepatology 2000;31:101-108
25 Everett L, Galli A, Crabb D. The role of hepatic peroxisome proliferator-activated receptors (PPARs) in health and
disease. Liver 2000;20:191-199
26 Marra F, Efsen E, Romanelli RG, Caligiuri A, Pastacaldi S, Batignani G, Bonacchi A, Caporale R, Laffi G, Pinzani M,Gentilini P. Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory
, http://www.100md.com
actions in hepatic stellate cells. Gastroenterology 2000;119:466-478
27 Dubuquoy L, Dharancy S, Nutten S, Pettersson S, Auwerx J, Desreumaux P. Role of peroxisome proliferator-activated
receptor gamma and retinoid X receptor heterodimer in hepatogastroenterological diseases. Lancet
2002;360:1410-1418
28 Miyahara T, Schrum L, Rippe R, Xiong S, Yee HF Jr, Motomura K, Anania FA, Willson TM, Tsukamoto H. Peroxisome
, http://www.100md.com
proliferator-activated receptors and hepatic stellate cell activation. J Biol Chem 2000;275:35715-35722
29 Sung CK, She H, Xiong S, Tsukamoto H. Tumor necrosis factor-alpha inhibits peroxisome proliferator-activated
receptor gamma activity at a posttranslational level in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol
2004;286:G722-729
30 She H, Xiong S, Hazra S, Tsukamoto H. Adipogenic transcriptional regulation of hepatic stellate cells.
, http://www.100md.com
J Biol Chem 2005;280:4959-4967
31 Allenby G, Bocquel MT, Saunders M, Kazmer S, Speck J, Rosenberger M, Lovey A, Kastner P, Grippo JF, Chambon P.
Retinoic acid receptors and retinoid X receptors:interactions with endogenous retinoic acids. Proc Natl Acad Sci USA
1993;90:30-34
32 Sande S, Sharif M, Chen H, Privalsky M. v-erbA acts on retinoic acid receptors in immature avian erythroid cells.
, 百拇医药
J Virol 1993;67:1067-1074
33 Leid M, Kastner P, Chambon P. Multiplicity generates diversity in the retinoic acid signalling pathways.
Trends Biochem Sci 1992;17:427-433
34 Perlmann T, Evans RM. Nuclear receptors in Sicily:all in the famiglia. Cell 1997;90:391-397
35 Weiner FR, Blaner WS, Czaja MJ, Shah A, Geerts A. Ito cell expression of a nuclear retinoic acid receptor.
, http://www.100md.com
Hepatology 1992;15:336-342
36 Ohata M, Lin M, Satre M, Tsukamoto H. Diminished retinoic acid signaling in hepatic stellate cells in cholestatic
liver fibrosis. Am J Physiol 1997;272(3 Pt 1):G589- G596
37 Li H, Zhang JS, Huang GC, Zhang N, Chen Q, Zhang XR. Effect of RAR-beta transfection on the proliferation and
phenotype of rat hepatic stellate cells. Zhonghua Ganzangbing Zazhi 2002;10:297-300
, 百拇医药
38 Li H, Zhang J, Huang G, Zhang N, Chen Q, Zhang X. Effect of retinoid kappa receptor alpha(RXRalpha)transfection on
the proliferation and phenotype of rat hepatic stellate cells in vitro. Chin Med J (Engl) 2002;115:928-932
39 Chen C, Zhang J, Li J, Huang J, Yang C, Huang G, Shi J. Hydrodynamic-based in vivo transfection of retinoic X
receptor-alpha gene can enhance vitamin A-induced attenuation of liver fibrosis in mice. Liver Int 2004;24:679-686
, http://www.100md.com
40 Juge-Aubry CE, Gorla-Bajszczak A, Pernin A, Lemberger T, Wahli W, Burger AG, Meier CA. Peroxisome
proliferator-activated receptor mediates cross-talk with thyroid hormone receptor by competition for retinoid X receptor.
Possible role of a leucine zipper-like heptad repeat. J Biol Chem 1995;270:18117-18122
编辑 张海宁, 百拇医药
张锦生,男, 1944-3-14生, 江苏省镇江市人, 汉族. 1968年原上海第一医学院医学系毕业, 1985年原上海医科大学博士学位. 教授, 博士生导师, 主要从事肝病病理研究.
国家自然科学基金资助项目, No. 39970337, N0. 30170417
通讯作者:张锦生, 200032, 上海市医学院路138号, 复旦大学上海医学院病理学系. jszhang44@shmu.edu.cn
电话: 021-54237049 传真: 021-54237539
, 百拇医药
收稿日期: 2004-12-27 接受日期: 2005-03-02
摘要激活的肝星状细胞是肝纤维化时产生细胞外基质的主要细胞.细胞因子的旁分泌和自分泌作用、氧化应激、微环境ECM的改变是激活肝星状细胞的主要外部机制，激活时最初的显著变化是细胞质内脂滴和维生素A减少甚至消失，并表达a-平滑肌肌动蛋白.脂滴(含中性脂肪)的存在意味着向脂肪细胞分化，肝星状细胞向脂肪细胞分化及去分化与其激活有何关联，是激活时重要的分子机制之一，还是仅仅为一种伴随现象？最近的工作表明，与脂肪细胞分化密切相关的C/EBP-a和PPARg基因表达下调及维生素A信号转导削弱是肝星状细胞激活的重要内在机制.如果能从肝星状细胞激活的外部和内在机制两方面都进行干预的话，有可能提高肝纤维化的疗效.
关键词:肝星状细胞; 肝纤维化;激活
张锦生. 肝星状细胞激活的内在机制. 世界华人消化杂志 2005;13(7):831-8341 Friedman SL. Liver fibrosis-from bench to bedside. J Hepatol 2003;38(Suppl 1):S38-53
, 百拇医药
2 Friedman SL. Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis.
Mechanisms and treatment strategies. N Engl J Med 1993;328:1828-1835
3 Lee KS, Buck M, Houglum K, Chojkier M. Activation of hepatic stellate cells by TGF alpha and collagen type I is mediated
by oxidative stress through c-myb expression. J Clin Invest 1995;96:2461-2468
, 百拇医药
4 Friedman SL, Roll FJ, Boyles J, Arenson DM, Bissell DM. Maintenance of differentiated phenotype of cultured rat hepatic
lipocytes by basement membrane matrix. J Biol Chem 1989;264:10756-10762
5 Meyer DH, Krull N, Dreher KL, Gressner AM. Biglycan and decorin gene expression in normal and fibrotic rat liver:cellular
localization and regulatory factors. Hepatology 1992;16:204-216
, 百拇医药
6 Roskams T, Moshage H, De Vos R, Guido D, Yap P, Desmet V. Heparan sulfate proteoglycan expression in normal
human liver. Hepatology 1995;21:950-958
7 Musso O, Rehn M, Saarela J, Theret N, Lietard J, Hintikka, Lotrian D, Campion JP, Pihlajaniemi T, Clement B. Collagen
XVIII is localized in sinusoids and basement membrane zones and expressed by hepatocytes and activated stellate cells
, 百拇医药
in fibrotic human liver. Hepatology 1998;28:98-107
8 Geerts A. History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells.
Semin Liver Dis 2001;21:311-335
9 Yokoi Y, Namihisa T, Kuroda H, Komatsu I, Miyazaki A, Watanabe S, Usui K. Immunocytochemical detection of desmin
in fat-storing cells(Ito cells). Hepatology 1984;4:709-714
, 百拇医药
10 Gard AL, White FP, Dutton GR. Extra-neural glial fibrillary acidic protein(GFAP)immunoreactivity in perisinusoidal
stellate cells of rat liver. J Neuroimmunol 1985;8:359-375
11 Ramadori G, Veit T, Schwogler S, Dienes HP, Knittel T, Rieder H, Meyer zum Buschenfelde KH. Expression of the gene
of the alpha-smooth muscle-actin isoform in rat liver and in rat fat-storing(ITO)cells.
, 百拇医药
Virchows Arch B Cell Pathol Incl Mol Pathol 1990;59:349-357
12 Enzan H, Himeno H, Iwamura S, Saibara T, Onishi S, Yamamoto Y, Hara H. Immunohistochemical identification of Ito
cells and their myofibroblastic transformation in adult human liver. Virchows Arch 1994;424:249-256
13 Suskind DL, Muench MO. Searching for common stem cells of the hepatic and hematopoietic systems in the human
, http://www.100md.com
fetal liver:CD34+ cytokeratin 7/8+ cells express markers for stellate cells. J Hepatol 2004;40:261-268
14 Cassiman D, van Pelt J, De Vos R, Van Lommel F, Desmet V, Yap SH, Roskams T. Synaptophysin:A novel marker
for human and rat hepatic stellate cells. Am J Pathol 1999;155:1831-1839
15 Cassiman D, Denef C, Desmet VJ, Roskams T. Human and rat hepatic stellate cells express neurotrophins and
, 百拇医药
neurotrophin receptors. Hepatology 2001;33:148-158
16 Trim N, Morgan S, Evans M, Issa R, Fine D, Afford S, Wilkins B, Iredale J. Hepatic stellate cells express the low
affinity nerve growth factor receptor p75 and undergo apoptosis in response to nerve growth factor stimulation.
Am J Pathol 2000;156:1235-1243
17 Johnson PF, Landschulz WH, Graves BJ, McKnight SL. Identification of a rat liver nuclear protein that binds to the
, 百拇医药
enhancer core element of three animal viruses. Genes Dev 1987;1:133-146
18 黄光存, 张锦生.CCAAT/增强子结合蛋白家族与肝脏疾病.中华肝脏病杂志 2003;11:57-59
19 Tang QQ, Jiang MS, Lane MD. Repressive effect of Sp1 on the C/EBPalpha gene promoter:role in adipocyte
differentiation. Mol Cell Biol 1999;19:4855-4865
20 Huang GC, Zhang JS, Tang QQ. Involvement of C/EBP-alpha gene in in vitro activation of rat hepatic stellate cells.
, 百拇医药
Biochem Biophys Res Commun 2004;324:1309-1318
21 Huang J, Zhang JS, Huang GC, Tang QQ, Chen C, Zhang XR, Chen Q. Expression of CCAAT/enhancer-binding protein
in cultured rat hepatic stellate cells and its significance. Zhonghua Ganzangbing Zazhi 2004;12:259-262
22 Takiguchi M. The C/EBP family of transcription factors in the liver and other organs. Int J Exp Pathol 1998;79:369-391
, 百拇医药
23 Vanden Heuvel JP. Peroxisome proliferator-activated receptors:a critical link among fatty acids, gene expression and
carcinogenesis. J Nutr 1999;129(2S Suppl):575S-580S
24 Galli A, Crabb D, Price D, Ceni E, Salzano R, Surrenti C, Casini A. Peroxisome proliferator-activated receptor gamma
transcriptional regulation is involved in platelet-derived growth factor-induced proliferation of human hepatic stellate
, 百拇医药
cells. Hepatology 2000;31:101-108
25 Everett L, Galli A, Crabb D. The role of hepatic peroxisome proliferator-activated receptors (PPARs) in health and
disease. Liver 2000;20:191-199
26 Marra F, Efsen E, Romanelli RG, Caligiuri A, Pastacaldi S, Batignani G, Bonacchi A, Caporale R, Laffi G, Pinzani M,Gentilini P. Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory
, http://www.100md.com
actions in hepatic stellate cells. Gastroenterology 2000;119:466-478
27 Dubuquoy L, Dharancy S, Nutten S, Pettersson S, Auwerx J, Desreumaux P. Role of peroxisome proliferator-activated
receptor gamma and retinoid X receptor heterodimer in hepatogastroenterological diseases. Lancet
2002;360:1410-1418
28 Miyahara T, Schrum L, Rippe R, Xiong S, Yee HF Jr, Motomura K, Anania FA, Willson TM, Tsukamoto H. Peroxisome
, http://www.100md.com
proliferator-activated receptors and hepatic stellate cell activation. J Biol Chem 2000;275:35715-35722
29 Sung CK, She H, Xiong S, Tsukamoto H. Tumor necrosis factor-alpha inhibits peroxisome proliferator-activated
receptor gamma activity at a posttranslational level in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol
2004;286:G722-729
30 She H, Xiong S, Hazra S, Tsukamoto H. Adipogenic transcriptional regulation of hepatic stellate cells.
, http://www.100md.com
J Biol Chem 2005;280:4959-4967
31 Allenby G, Bocquel MT, Saunders M, Kazmer S, Speck J, Rosenberger M, Lovey A, Kastner P, Grippo JF, Chambon P.
Retinoic acid receptors and retinoid X receptors:interactions with endogenous retinoic acids. Proc Natl Acad Sci USA
1993;90:30-34
32 Sande S, Sharif M, Chen H, Privalsky M. v-erbA acts on retinoic acid receptors in immature avian erythroid cells.
, 百拇医药
J Virol 1993;67:1067-1074
33 Leid M, Kastner P, Chambon P. Multiplicity generates diversity in the retinoic acid signalling pathways.
Trends Biochem Sci 1992;17:427-433
34 Perlmann T, Evans RM. Nuclear receptors in Sicily:all in the famiglia. Cell 1997;90:391-397
35 Weiner FR, Blaner WS, Czaja MJ, Shah A, Geerts A. Ito cell expression of a nuclear retinoic acid receptor.
, http://www.100md.com
Hepatology 1992;15:336-342
36 Ohata M, Lin M, Satre M, Tsukamoto H. Diminished retinoic acid signaling in hepatic stellate cells in cholestatic
liver fibrosis. Am J Physiol 1997;272(3 Pt 1):G589- G596
37 Li H, Zhang JS, Huang GC, Zhang N, Chen Q, Zhang XR. Effect of RAR-beta transfection on the proliferation and
phenotype of rat hepatic stellate cells. Zhonghua Ganzangbing Zazhi 2002;10:297-300
, 百拇医药
38 Li H, Zhang J, Huang G, Zhang N, Chen Q, Zhang X. Effect of retinoid kappa receptor alpha(RXRalpha)transfection on
the proliferation and phenotype of rat hepatic stellate cells in vitro. Chin Med J (Engl) 2002;115:928-932
39 Chen C, Zhang J, Li J, Huang J, Yang C, Huang G, Shi J. Hydrodynamic-based in vivo transfection of retinoic X
receptor-alpha gene can enhance vitamin A-induced attenuation of liver fibrosis in mice. Liver Int 2004;24:679-686
, http://www.100md.com
40 Juge-Aubry CE, Gorla-Bajszczak A, Pernin A, Lemberger T, Wahli W, Burger AG, Meier CA. Peroxisome
proliferator-activated receptor mediates cross-talk with thyroid hormone receptor by competition for retinoid X receptor.
Possible role of a leucine zipper-like heptad repeat. J Biol Chem 1995;270:18117-18122
编辑 张海宁, 百拇医药
