Semin Liver Dis 2001; 21(3): 385-396
DOI: 10.1055/s-2001-17553
Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Transcriptional Regulation in Hepatic Stellate Cells

Francis J. Eng, Scott L. Friedman
  • Division of Liver Diseases and Department of Medicine, Mount Sinai School of Medicine, New York, New York
Further Information

Publication History

Publication Date:
01 October 2001 (online)


Modulation of gene expression through altered transcription regulates stellate cell behavior in normal liver and following hepatic injury. Transcription factors are generally classified according to conserved motifs within either the activation- or DNA- binding domains of the molecules. Transcriptional activity in stellate cells represents a delicate fine tuning of multiple inputs. Activities of these transcription factors are modified by their intracellular localization, rate and pathway of degradation, oligomerization, and interactions with heterologous factors and chromatin, as well as by posttranslational modifications, including phosphorylation, glycosylation, and acetylation. General paradigms of transcriptional control are increasingly being validated in hepatic stellate cells, particularly involving the transcription factors CCAAT/enhancer-binding proteins, c-myb, CREB, nuclear factor κB, peroxisome proliferator-activated receptor, and Kruppel-like zinc finger factors. Although there are no simple rules that govern mechanisms of transcriptional regulation in stellate cells, continued advances will yield new insights into their role in normal liver homeostasis and in the response to injury.


  • 1 Li D, Friedman S L. Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy.  J Gastroenterol Hepatol . 1999;  14 618-633
  • 2 Olaso E, Friedman S L. Molecular regulation of hepatic fibrogenesis.  J Hepatol . 1998;  29 836-847
  • 3 Bissell D M. Lipocyte activation and hepatic fibrosis.  Gastroenterology . 1992;  102 1803-1805
  • 4 Friedman S L, Wei S, Blaner W S. Retinol release by activated rat hepatic lipocytes: regulation by Kupffer cell-conditioned medium and PDGF.  Am J Physiol . 1993;  264 947-952
  • 5 Tsukamoto H, Cheng S, Blaner W S. Effects of dietary polyunsaturated fat on ethanol-induced Ito cell activation.  Am J Physiol . 1996;  270 G581-586
  • 6 Rockey D C, Boyles J K, Gabbiani G, Friedman S L. Rat hepatic lipocytes express smooth muscle actin upon activation in vivo and in culture.  J Submicrosc Cytol Pathol . 1992;  24 193-203
  • 7 Goodrich J A, Cutler G, Tjian R. Contacts in context: promoter specificity and macromolecular interactions in transcription.  Cell . 1996;  84 825-830
  • 8 Calkhoven C F, Ab G. Multiple steps in the regulation of transcription-factor level and activity.  Biochem J . 1996;  317 329-342
  • 9 Lemon B, Tjian R. Orchestrated response: a symphony of transcription factors for gene control.  Genes Dev . 2000;  14 2551-2569
  • 10 Inagaki Y, Mamura M, Kanamaru Y. Constitutive phosphorylation and nuclear localization of Smad3 are correlated with increased collagen gene transcription in activated hepatic stellate cells.  J Cell Physiol . 2001;  187 117-123
  • 11 Lefstin J A, Yamamoto K R. Allosteric effects of DNA on transcriptional regulators.  Nature . 1998;  392 885-888
  • 12 Buschmann T, Fuchs S Y, Lee C G, Pan Z Q, Ronai Z. SUMO-1 modification of Mdm2 prevents its self-ubiquitination and increases Mdm2 ability to ubiquitinate p53.  Cell . 2000;  101 753-762
  • 13 Lakin N D, Jackson S P. Regulation of p53 in response to DNA damage.  Oncogene . 1999;  18 7644-7655
  • 14 Berk A J. Regulation of eukaryotic transcription factors by post-translational modification.  Biochim Biophys Acta . 1989;  1009 103-109
  • 15 Ito A, Lai C H, Zhao X. p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2.  EMBO J . 2001;  20 1331-1340
  • 16 Appella E, Anderson C W. Signaling to p53: breaking the posttranslational modification code.  Pathol Biol (Paris) . 2000;  48 227-245
  • 17 Comer F I, Hart G W. O-GlcNAc and the control of gene expression.  Biochim Biophys Acta . 1999;  1473 161-171
  • 18 Klug A, Schwabe J W. Protein motifs 5. Zinc fingers.  FASEB J . 1995;  9 597-604
  • 19 Leon O, Roth M. Zinc fingers: DNA binding and protein-protein interactions.  Biol Res . 2000;  33 21-30
  • 20 Mackay J P, Crossley M. Zinc fingers are sticking together.  Trends Biochem Sci . 1998;  23 1-4
  • 21 Fry C J, Peterson C L. Chromatin remodeling enzymes: who's on first?.  Curr Biol . 2001;  11 R185-197
  • 22 Friedman S L. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury.  J Biol Chem . 2000;  275 2247-2250
  • 23 Greenwel P, Dominguez-Rosales J A, Mavi G, Rivas-Estilla A M, Rojkind M. Hydrogen peroxide: a link between acetaldehyde-elicited alpha1(I) collagen gene up-regulation and oxidative stress in mouse hepatic stellate cells.  Hepatology . 2000;  31 109-116
  • 24 Iraburu M J, Dominguez-Rosales J A, Fontana L. Tumor necrosis factor alpha down-regulates expression of the alpha1(I) collagen gene in rat hepatic stellate cells through a p20C/EBPbeta- and C/EBPdelta-dependent mechanism.  Hepatology . 2000;  31 1086-1093
  • 25 Garcia-Trevijano E R, Iraburu M J, Fontana L. Transforming growth factor beta1 induces the expression of alpha1(I) procollagen mRNA by a hydrogen peroxide-C/EBPbeta-dependent mechanism in rat hepatic stellate cells.  Hepatology . 1999;  29 960-970
  • 26 Lekstrom-Himes J, Xanthopoulos K G. Biological role of the CCAAT/enhancer-binding protein family of transcription factors.  J Biol Chem . 1998;  273 28545-28548
  • 27 Diehl A M. Roles of CCAAT/enhancer-binding proteins in regulation of liver regenerative growth.  J Biol Chem . 1998;  273 30843-30846
  • 28 Kaplowitz N, Tsukamoto H. Oxidative stress in liver disease.  Prog Liver Dis . 1996;  14 131-160
  • 29 Bedossa P, Paradis V. Transforming growth factor-beta (TGF-beta): a key-role in liver fibrogenesis.  J Hepatol . 1995;  22 37-42
  • 30 Lieber C S. Cytochrome P-4502E1: its physiological and pathological role.  Physiol Rev . 1997;  77 517-544
  • 31 Lieber C S. Role of oxidative stress and antioxidant therapy in alcoholic and nonalcoholic liver diseases.  Adv Pharmacol . 1997;  38 601-628
  • 32 Greenwel P. Acetaldehyde-mediated collagen regulation in hepatic stellate cells.  Alcohol Clin Exp Res . 1999;  23 930-933
  • 33 Lincoln A J, Monczak Y, Williams S C, Johnson P F. Inhibition of CCAAT/enhancer-binding protein alpha and beta translation by upstream open reading frames.  J Biol Chem . 1998;  273 9552-9560
  • 34 Welm A L, Timchenko N A, Darlington G J. C/EBPalpha regulates generation of C/EBPbeta isoforms through activation of specific proteolytic cleavage.  Mol Cell Biol . 1999;  19 1695-1704
  • 35 Knittel T, Mehde M, Kobold D, Saile B, Dinter C, Ramadori G. Expression patterns of matrix metalloproteinases and their inhibitors in parenchymal and non-parenchymal cells of rat liver: regulation by TNF-alpha and TGF-beta1.  J Hepatol . 1999;  30 48-60
  • 36 Stocker W, Grams F, Baumann U. The metzincins-topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases.  Protein Sci . 1995;  4 823-840
  • 37 Lee K S, 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
  • 38 Buck M, Kim D J, Houglum K, Hassanein T, Chojkier M. c-Myb modulates transcription of the alpha-smooth muscle actin gene in activated hepatic stellate cells.  Am J Physiol Gastrointest Liver Physiol . 2000;  278 G321-328
  • 39 Houglum K, Venkataramani A, Lyche K, Chojkier M. A pilot study of the effects of d-alpha-tocopherol on hepatic stellate cell activation in chronic hepatitis C.  Gastroenterology . 1997;  113 1069-1073
  • 40 Houglum K, Lee K S, Chojkier M. Proliferation of hepatic stellate cells is inhibited by phosphorylation of CREB on serine 133.  J Clin Invest . 1997;  99 1322-1328
  • 41 Verma I M, Stevenson J K, Schwarz E M, Van Antwerp D, Miyamoto S. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation.  Genes Dev . 1995;  9 2723-2735
  • 42 DiDonato J A, Hayakawa M, Rothwarf D M, Zandi E, Karin M. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB.  Nature . 1997;  388 548-554
  • 43 Zhong H, Voll R E, Ghosh S. Phosphorylation of NF-kappa B p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/ p300.  Mol Cell . 1998;  1 661-671
  • 44 Zhong H, SuYang H, Erdjument-Bromage H, Tempst P, Ghosh S. The transcriptional activity of NF-kappaB is regulated by the IkappaB-associated PKAc subunit through a cyclic AMP-independent mechanism.  Cell . 1997;  89 413-424
  • 45 Hellerbrand C, Jobin C, Licato L L, Sartor R B, Brenner D A. Cytokines induce NF-kappaB in activated but not in quiescent rat hepatic stellate cells.  Am J Physiol . 1998;  275 G269-278
  • 46 Rippe R A, Schrum L W, Stefanovic B, Solis-Herruzo J A, Brenner D A. NF-kappaB inhibits expression of the alpha1(I) collagen gene.  DNA Cell Biol . 1999;  18 751-761
  • 47 Elsharkawy A M, Wright M C, Hay R T. Persistent activation of nuclear factor-kappaB in cultured rat hepatic stellate cells involves the induction of potentially novel Rel-like factors and prolonged changes in the expression of IkappaB family proteins.  Hepatology . 1999;  30 761-769
  • 48 Lang A, Schoonhoven R, Tuvia S, Brenner D A, Rippe R A. Nuclear factor kappaB in proliferation, activation, and apoptosis in rat hepatic stellate cells.  J Hepatol . 2000;  33 49-58
  • 49 Hellerbrand C, Jobin C, Iimuro Y, Licato L, Sartor R B, Brenner D A. Inhibition of NFkappaB in activated rat hepatic stellate cells by proteasome inhibitors and an IkappaB super-repressor [Comments].  Hepatology . 1998;  27 1285-1295
  • 50 Hernandez I, de la Torre P, Rey-Campos J. Collagen alpha1(I) gene contains an element responsive to tumor necrosis factor-alpha located in the 5′ untranslated region of its first exon.  DNA Cell Biol . 2000;  19 341-352
  • 51 Gallois C, Habib A, Tao J. Role of NF-kappaB in the antiproliferative effect of endothelin-1 and tumor necrosis factor-alpha in human hepatic stellate cells. Involvement of cyclooxygenase-2.  J Biol Chem . 1998;  273 23183-190
  • 52 Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease.  Nature . 2000;  405 421-424
  • 53 Everett L, Galli A, Crabb D. The role of hepatic peroxisome proliferator-activated receptors (PPARs) in health and disease.  Liver . 2000;  20 191-199
  • 54 Rosen E D, Walkey C J, Puigserver P, Spiegelman B M. Transcriptional regulation of adipogenesis.  Genes Dev . 2000;  14 1293-1307
  • 55 Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat.  Endocrinology . 1996;  137 354-366
  • 56 Miyahara T, Schrum L, Rippe R. Peroxisome proliferator-activated receptors and hepatic stellate cell activation.  J Biol Chem . 2000;  275 35715-35722
  • 57 Marra F, Efsen E, Romanelli R G. Ligands of peroxisome-proliferator activated receptor gamma modulate profibrogenic and proinflammatory actions of hepatic stellate cells.  Gastroenterology . 2000;  119 466-478
  • 58 Galli A, Crabb D, Price D. Peroxisome proliferator-activated receptor gamma transcriptional regulation is involved in platelet-derived growth factor-induced proliferation of human hepatic stellate cells.  Hepatology . 2000;  31 101-108
  • 59 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 G589-596
  • 60 Dang D T, Pevsner J, Yang V W. The biology of the mammalian Kruppel-like family of transcription factors.  Int J Biochem Cell Biol . 2000;  32 1103-1121
  • 61 Ratziu V, Lalazar A, Wong L. Zf9, a Kruppel-like transcription factor up-regulated in vivo during early hepatic fibrosis.  Proc Natl Acad Sci U S A . 1998;  95 9500-9505
  • 62 Inuzuka H, Wakao H, Masuho Y, Muramatsu M A, Tojo H, Nanbu-Wakao R. cDNA cloning and expression analysis of mouse zf9, a Kruppel-like transcription factor gene that is induced by adipogenic hormonal stimulation in 3T3-L1 cells.  Biochim Biophys Acta . 1999;  1447 199-207
  • 63 Inuzuka H, Nanbu-Wakao R, Masuho Y, Muramatsu M, Tojo H, Wakao H. Differential regulation of immediate early gene expression in preadipocyte cells through multiple signaling pathways.  Biochem Biophys Res Commun . 1999;  265 664-668
  • 64 Ratziu R, Kim S J, Kim Y S, Dang S, Wong L, Friedman S L. A key role for Zf9 in hepatic fibrosis via its transcriptional activation of TGFb1 and types I and II TGFb receptors genes in rat stellate cells [Abstract].  Hepatology . 1997;  26 185
  • 65 Kojima S, Hayashi S, Shimokado K. Transcriptional activation of urokinase by the Kruppel-like factor Zf9/COPEB activates latent TGF-beta1 in vascular endothelial cells.  Blood . 2000;  95 1309-1316
  • 66 Zhao J L, Austen K F, Lam B K. Cell-specific transcription of leukotriene C(4) synthase involves a Kruppel-like transcription factor and Sp1.  J Biol Chem . 2000;  275 8903-8910
  • 67 Beno D W, Mullen J, Davis B H. Lipoxygenase inhibitors block PDGF-induced mitogenesis: a MAPK-independent mechanism that blocks fos and egr.  Am J Physiol . 1995;  268 C604-610
  • 68 Bigby T D. The leukotriene C(4) synthase gene and asthma.  Am J Respir Cell Mol Biol . 2000;  23 273-276
  • 69 Chen A, Beno D W, Davis B H. Suppression of stellate cell type I collagen gene expression involves AP-2 transmodulation of nuclear factor-1-dependent gene transcription.  J Biol Chem . 1996;  271 25994-25998
  • 70 Chen A, Davis B. The DNA binding protein BTEB mediates acetaldehyde-induced, jun N-terminal kinase-dependent alphaI(I) collagen gene expression in rat hepatic stellate cells [In Process Citation].  Mol Cell Biol . 2000;  20 2818-2826
  • 71 Denver R J, Ouellet L, Furling D, Kobayashi A, Fujii-Kuriyama Y, Puymirat J. Basic transcription element-binding protein (BTEB) is a thyroid hormone-regulated gene in the developing central nervous system. Evidence for a role in neurite outgrowth.  J Biol Chem . 1999;  274 23128-23134
  • 72 Oren R, Dabeva M D, Karnezis A N. Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes.  Hepatology . 1999;  30 903-913
  • 73 Rippe R A, Almounajed G, Brenner D A. Sp1 binding activity increases in activated Ito cells.  Hepatology . 1995;  22 241-251
  • 74 Ruiz I G, de la Torre P, Diaz T. Sp family of transcription factors is involved in iron-induced collagen alpha1(I) gene expression.  DNA Cell Biol . 2000;  19 167-178
  • 75 Kawada N, Uoya M, Seki S, Kuroki T, Kobayashi K. Regulation by cAMP of STAT1 activation in hepatic stellate cells.  Biochem Biophys Res Commun . 1997;  233 464-469
  • 76 Marra F, Arrighi M C, Fazi M. Extracellular signal-regulated kinase activation differentially regulates platelet-derived growth factor's actions in hepatic stellate cells, and is induced by in vivo liver injury in the rat.  Hepatology . 1999;  30 951-958
  • 77 Dooley S, Delvoux B, Lahme B, Mangasser-Stephan K, Gressner A M. Modulation of transforming growth factor beta response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts.  Hepatology . 2000;  31 1094-1106
  • 78 Inagaki Y, Nemoto T, Nakao A. Interaction between GC box binding factors and Smad proteins modulates cell lineage-specific alpha 2(I) collagen gene transcription.  J Biol Chem . 2001;  5 5
  • 79 Knittel T, Kobold D, Dudas J, Saile B, Ramadori G. Role of the Ets-1 transcription factor during activation of rat hepatic stellate cells in culture.  Am J Pathol . 1999;  155 1841-1848
  • 80 Parola M, Robino G, Marra F. HNE interacts directly with JNK isoforms in human hepatic stellate cells.  J Clin Invest . 1998;  102 1942-1950
  • 81 Bahr M J, Vincent K J, Arthur M J. Control of the tissue inhibitor of metalloproteinase1 promoter in culture-activated rat hepatic stellate cells: regulation by activator protein-1 DNA binding proteins.  Hepatology . 1999;  29 839-48