Krüppel-like Factors and the Liver

  • Goutham Narla
  • Scott L. Friedman


The Krüppel-like zinc finger transcription factor family encodes a family of proteins that currently includes at least 15 members regulating remarkably diverse processes, including cell growth, signal transduction, and differentiation. KLF genes are highly conserved evolutionarily with homologues expressed in zebrafish and Xenopus. The role of the Krüppel-like factor (KLF) family in the liver is equally diverse, with roles in the regulation of adipogenesis, gluconeogen-esis, apoptosis, cell cycle progression, cellular differentiation, energy homeostasis, oxidative stress, and hepatic stellate cell activation. Of the KLFs studied to date in the liver, KLF6 is the best characterized. This chapter therefore highlights the functional diversity of KLF6 in the liver with the understanding that it serves as a template for the study of other KLFs in the liver. Specifically, we focus on the KLF6 gene and its cloning and identification from activated hepatic stellate cells, the importance of alternative splicing in the regulation of KLF6 gene function, the contribution of the KLF family to liver development and injury, and finally, dysregulation of KLF6 function in disease through several important mechanisms including alternative splicing, decreased expression, loss of heterozygosity, and somatic mutation.


Alternative Splice Hepatic Stellate Cell Nonalcoholic Fatty Liver Disease Definitive Endoderm Hepatic Stellate Cell Activation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Banerjee SS, Feinberg MW, Wantanabe M, Gray S, Haspel RL, Denkinger DJ, Kawahara R, Hauner H, Jain MK (2003) The Kruppel-like factor KLF2 inhibits peroxisome proliferator-activated receptor-gamma expression and adipogenesis. J Biol Chem. 278:2581–2584.PubMedCrossRefGoogle Scholar
  2. Birsoy K, Chen Z, Friedman J (2008) Transcriptional regulation of adipogenesis by KLF4. Cell Metab. 7:339–347.PubMedCrossRefGoogle Scholar
  3. Blanchon L, Bocco JL, Gallot D, et al (2001) Co-localization of KLF6 and KLF4 with pregnancy-specific glycoproteins during human placenta development. Mech Dev. 105:185–189.PubMedCrossRefGoogle Scholar
  4. Botella LM, Sanchez-Elsner T, Sanz-Rodriguez F, et al (2002) Transcriptional activation of endoglin and transforming growth factor-beta signaling components by cooperative interaction between Sp1 and KLF6: their potential role in the response to vascular injury. Blood 100:4001–4010.PubMedCrossRefGoogle Scholar
  5. Cáceres JF, Kornblihtt AR (2002) Alternative splicing: multiple control mechanisms and involvement in human disease. Trends Genet. 18:186–193.PubMedCrossRefGoogle Scholar
  6. Camacho-Vanegas O, Narla G, Teixeira MS, et al (2007) Functional inactivation of the KLF6 tumor suppressor gene by loss of heterozygosity and increased alternative splicing in glioblas-toma. Int. J. Cancer 121:1390–1395.PubMedCrossRefGoogle Scholar
  7. Chiambaretta F, Blanchon L, Rabier B, et al (2002) Regulation of corneal keratin-12 gene expression by the human Kruppel-like transcription factor 6. Invest. Ophthalmol. Vis. Sci. 43:3422–3429.PubMedGoogle Scholar
  8. Dang DT, Pevsner J, Yang VW (2000) The biology of the mammalian Krüppel-like family of transcription factors. Int. J. Biochem. Cell Biol. 32:1103–1121.PubMedCrossRefGoogle Scholar
  9. Das A, Fernandez-Zapico, ME, Cao S, et al (2006) Disruption of an SP2/KLF6 repression complex by SHP is required for farnesoid X receptor-induced endothelial cell migration. J. Biol. Chem. 281:39105–39113.PubMedCrossRefGoogle Scholar
  10. De Graeve F, Smaldone S, Laub F, et al (2003) Identification of the Drosophila progenitor of mammalian Kruppel-like factors 6 and 7 and a determinant of fly development. Gene.314:55–62.PubMedCrossRefGoogle Scholar
  11. DiFeo A, Feld L, Rodriguez E, et al (2008) A functional role for KLF6-SV1 in lung adenocarcinoma prognosis and chemotherapy response. Cancer Res. 68:965–970.PubMedCrossRefGoogle Scholar
  12. DiFeo A, Narla G, Camacho-Vanegas O, et al (2006a) E-cadherin is a novel transcriptional target of the KLF6 tumor suppressor. Oncogene 25:6026–6031.CrossRefGoogle Scholar
  13. El Rouby S, Newcomb EW (1996) Identification of Bcd, a novel proto-oncogene expressed in B-cells. Oncogene. 13(12):2623–2630.PubMedGoogle Scholar
  14. Faustino NA, Cooper TA (2003) Pre-mRNA splicing and human disease. Genes Dev. 17:419–437.PubMedCrossRefGoogle Scholar
  15. Fischer EA, Verpont MC, Garrett-Sinha LA, et al (2001) Klf6 is a zinc finger protein expressed in a cell-specific manner during kidney development. J Am Soc Nephrol. 12:726–735.PubMedGoogle Scholar
  16. Friedman SL (2006) Transcrptional regulation of stellate cell activation. J Gastroenterol Hepatol, 21:S79–83.PubMedCrossRefGoogle Scholar
  17. Friedman SL (2008) Hepatic Stellate Cells — Protean, Multifunctional, and Enigmatic Cells of the Liver. Physiological Reviews. 88:125–172.PubMedCrossRefGoogle Scholar
  18. Garcia-Blanco MA, Baraniak AP, Lasda EL (2004) Alternative splicing in disease and therapy. Nat. Biotechnol. 22:535–546.PubMedCrossRefGoogle Scholar
  19. Gloor H, (1950) Arch. Julius Klaus-Stift. 25:38–44.Google Scholar
  20. Gouon-Evans V, Boussemart L, Gadue P, et al (2006) BMP-4 is required for hepatic specification of mouse embryonic stem cell-derived definitive endoderm. Nat Biotechnol. 24:1402–1411.PubMedCrossRefGoogle Scholar
  21. Gray S, Wang B, Orihuela Y, et al (2007) Regulation of gluconeogenesis by Kruppel-like factor 15. Cell Metab 5:305–312.PubMedCrossRefGoogle Scholar
  22. Hashmi S, Ji Q, Zhang J, Parhar RS, Huang CH, Brey C, Gaugler R (2008) A Kruppel-like factor in Caenorhabditis elegans with essential roles in fat regulation, cell death, and phagocytosis. DNA Cell Biol. 27:545–551.PubMedCrossRefGoogle Scholar
  23. Hirasawa Y, Arai M, Imazeki F, et al (2007) Methylation status of genes upegulated by demethyl-ating agent 5-aza-2′-deoxycytidine in hepatocellular carcinoma. Oncology 71:77–85.Google Scholar
  24. Huber TL, Perkins AC, Deconinck AE et al (2001) Neptune, A Kruppel-like transcription factor that participates in primitive erythropoiesis in Xenopus. Curr Biol 11:1456–1461.PubMedCrossRefGoogle Scholar
  25. Inuzuka H, Nanbu-Wakao R, Masuho Y et al (1999) Differential regulation of immediate early gene expression in preadipocyte cells through multiple signaling pathways. Biochem. Biophys. Res. Commun. 265:664–668.PubMedCrossRefGoogle Scholar
  26. Kawamura Y, Tanaka Y, Kawamori R, et al (2006). Overexpression of Kruppel-like factor 7 regulates adipocytokine gene expressions in human adipocytes and inhibits glucose-induced insulin secretion in pancreatic beta-cell-line. Mol Endocrinol. 20:844–56.PubMedCrossRefGoogle Scholar
  27. Kim Y, Ratziu V, Choi SG, et al (1998) Transcriptional activation of transforming growth factor beta1 and its receptors by the Kruppel-like factor Zf9/core promoter-binding protein and Sp1. Potential mechanisms for autocrine fibrogenesis in response to injury. J. Biol. Chem. 273:33750–33758.PubMedCrossRefGoogle Scholar
  28. Kojima, S, Hayashi S, Shimokado K, et al (2000) Transcriptional activation of urokinase by the Kruppel-like factor Zf9/COPEB activates latent TGF-beta1 in vascular endothelial cells. Blood 95:1309–1316.PubMedGoogle Scholar
  29. Koritschoner NP, Bocco JL, Panzetta-Dutari GM, et al (1997) A novel human zinc finger protein that interacts with the core promoter element of a TATA box-less gene. J. Biol. Chem. 272:9573–9580.PubMedCrossRefGoogle Scholar
  30. Kremer-Tal S, Narla, G, Chen Y, et al (2007) Downregulation of KLF6 is an early event in hepa-tocarcinogenesis, and stimulates proliferation while reducing differentiation. J. Hepatol. 46:645–654.PubMedCrossRefGoogle Scholar
  31. Kuo CT, Veselits ML, Barton KP, et al (1997) The LKLF transcription factor is required for normal tunica media formation and blood vessel stabilization during murine embryogenesis. Genes Dev. 11:2996–3006.PubMedCrossRefGoogle Scholar
  32. Laub F, Aldabe R, Ramirez F, et al (2001a) Embryonic expression of Kruppel-like factor 6 in neural and non-neural tissues. Mech Dev.106:167–170.CrossRefGoogle Scholar
  33. Laub F, Aldabe R, Friedrich V, et al (2001b) Developmental expression of mouse Kruppel-like trnascription factor KLF7 suggests a potential role in neurogenesis. Dev Biol. 233:305–318.CrossRefGoogle Scholar
  34. Li D, Yea S, Dolios G, et al (2005) Kruppel-like factor-6 promotes preadipocyte differentiation through histone deacetylase 3-dependent repression of DLK1. J. Biol. Chem. 280:26941–26952.PubMedCrossRefGoogle Scholar
  35. Mann DA, Smart DE (2002) Transcriptional regulation of hepatic stellate cell activation. Gut 50:891–896.PubMedCrossRefGoogle Scholar
  36. Matsumoto, N., Kubo, A., Liu, H., Akita, K., Laub, F., et al., 2006. Developmental regulation of yolk sac hematopoiesis by Kruppel-like factor 6. Blood 107, 1357–1365.PubMedCrossRefGoogle Scholar
  37. Mercatante, DR, Mohler JL, Kole R (2002) Cellular response to an antisense-mediated shift of Bcl-x pre-mRNA splicing and antineoplastic agents. J. Biol. Chem. 277:49374–49382.PubMedCrossRefGoogle Scholar
  38. Miele L, Beale G, Patman G et al (2008) The Kruppel-like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease. 135:282–291.Google Scholar
  39. Narla G, DiFeo A, Reeves HL et al (2005b) A germline DNA polymorphism associated with increased prostate cancer risk enhances alternative splicing of the KLF6 tumor suppressor gene. Cancer Res. 65:1213–1222.CrossRefGoogle Scholar
  40. Narla G, Kremer-Tal S, Matsumoto N, et al (2007). In vivo regulation of p21 by the Kruppel-like factor 6 tumor suppressor gene in mouse liver and human hepatocellular carcinoma. Oncogene. 26:4428–4434.PubMedCrossRefGoogle Scholar
  41. Narla G, DiFeo A, Yao S, et al (2005a) Targeted inhibition of the KLF6 splice variant, KLF6 SV1, suppresses prostate cancer cell growth and spread. Cancer Res. 65:5761–5768.CrossRefGoogle Scholar
  42. Narla G, Heath KE, Reeves HL, et al (2001) KLF6, a candidate tumor suppressor gene mutated in prostate cancer. Science 294:2563–2566.PubMedCrossRefGoogle Scholar
  43. Oates, AC, Pratt, SJ, Vail, YI, et al (2001) The zebrafish klf gene family. Blood 98:1792–1801.PubMedCrossRefGoogle Scholar
  44. Oishi Y, Manabe I, Tobe K et al (2005) Kruppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation. Cell Metab 1:27–39.PubMedCrossRefGoogle Scholar
  45. Okano J, Opitz OG, Nakagawa H, et al (2000) The Kruppel-like transcriptional factors Zf9 and GKLF coactivate the human keratin 4 promoter and physically interact. FEBS Lett. 473:95–100.PubMedCrossRefGoogle Scholar
  46. Perkins AC, Sharpe AH, Orkin SH (1995) Lethal beta-thalassaemia in mice lacking the erythroid CACC-transcription factor EKLF. Nature. 375:318–322.PubMedCrossRefGoogle Scholar
  47. Philipsen S, Suske G (1999) A tale of three fingers: the family of mammalian Sp/XKLF transcription factors. Nucl. Acids Res. 27:2991–3000.PubMedCrossRefGoogle Scholar
  48. Ratziu V, Lalazar A, Wong L, et al (1998) Zf9, a Kruppel-like transcription factor up-regulated in vivo during early hepatic fibrosis. Proc Natl Acad Sci U S A. 95:9500–9505.PubMedCrossRefGoogle Scholar
  49. Segre JA, Bauer C, Fuchs E (1999) Klf4 is a transcription factor required for establishing the barrier function of the skin. Nat Genet. 22:356–360.PubMedCrossRefGoogle Scholar
  50. Shin C, Manley JL (2004) Cell signaling and the control of pre-mRNA splicing. Nat. Rev. Mol. Cell. Biol. 5:727–738.PubMedCrossRefGoogle Scholar
  51. Shindo T, Manabe I, Fukushima Y, et al (2002) Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling. Nat Med. 8:856–63.PubMedGoogle Scholar
  52. Sirach, E, Bureau, C, Peron JM, et al (2007) KLF6 transcription factor protects hepatocellular carcinoma-derived cells from apoptosis. Cell Death Differ. 14:1202–1210.PubMedCrossRefGoogle Scholar
  53. Song CZ, Keller K, Chen Y, et al (2003) Functional interplay between CBP and PCAF in acetylation and regulation of transcription factor KLF13 activity. J. Mol. Biol. 329:207–215.PubMedCrossRefGoogle Scholar
  54. Starkel P, Sempoux C, Leclercq I et al (2003) Oxidative stress, KLF6 and transforming growth factor-beta upregulation differentiate non-alcoholic steatohepatitis progressing to fibrosis from uncomplicated steatosis in rats. J Hepatol 39:538–46.PubMedCrossRefGoogle Scholar
  55. Sue N, Jack BH, Eaton SA et al (2008) Targeted disruption of the basic Kruppel-like factor gene (KLF3) reveals a role in adipogenesis. Mol Cell Biol. 28:3967–78.PubMedCrossRefGoogle Scholar
  56. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell;126:663–676.PubMedCrossRefGoogle Scholar
  57. Tal-Kremer S, Reeves HL, Narla, G, et al (2004) Frequent inactivation of the tumor suppressor Kruppel-like Factor 6 (KLF6) in hepatocellular carcinoma. Hepatology 40:1047–1052.CrossRefGoogle Scholar
  58. Teixeira MS, Camacho-Vanegas O, Fernandez Y, et al (2007) KLF6 allelic loss is associated with tumor recurrence and markedly decreased survival in head and neck squamous cell carcinoma. Int. J. Cancer 121:1976–1983.PubMedCrossRefGoogle Scholar
  59. Teshigawara K, Ogawa W, Mori T, et al (2005) Role of Kruppel-like factor 15 in PEPCK gene expression in the liver. Biochem Biophys Res Commun 327:920–926.PubMedCrossRefGoogle Scholar
  60. Ton-That H, Kaestner KH, Shields JM, et al (1997) Expression of the gut-enriched Kruppel-like factor gene during development and intestinal tumorigenesis. FEBS Lett. 419:239–243.PubMedCrossRefGoogle Scholar
  61. Turner J, Crossley M (1999) Mammalian Krüppel-like transcription factors: more than just a pretty finger. Trends Biochem. Sci. 24:236–240.PubMedCrossRefGoogle Scholar
  62. Wang S, Chen X, Zhang W, et al (2004) KLF6mRNA expression in primary hepatocellular carcinoma. J. Huazhong Univ. Sci. Technolog. Med. Sci. 24:585–587.PubMedGoogle Scholar
  63. Wu J, Srinivasan S, Neumann JC, et al (2005) The KLF2 transcription factor does not affect the formation of preadipocytes but inhibits their differentiation into adipocytes. Biochemistry 44:11098–11105.PubMedCrossRefGoogle Scholar
  64. Yea S, Narla G, Zhao X, et al (2008) Ras promotes growth by alternative splicing-mediated inac-tivation of the KLF6 tumor suppressor in hepatocellular carcinoma. Gastroenterology 134:1521–1531.PubMedCrossRefGoogle Scholar
  65. Zhang D, Zhang XL, Michel FJ, et al (2002) Direct interaction of the Kruppel-like family (KLF) member, BTEB1, and PR mediates progesterone-responsive gene expression in endometrial epithelial cells. Endocrinology 143:62–73.PubMedCrossRefGoogle Scholar
  66. Zhang W, Shields JM, Sogawa K, et al (1998) The gut-enriched Kruppel-like factor suppresses the activity of the CYP1A1 promoter in an Sp1-dependent fashion. J. Biol. Chem. 273:17917–17925.PubMedCrossRefGoogle Scholar
  67. Zhao JL, Austen KF, Lam BK (2000) Cell-specific transcription of leukotriene C(4) synthase involves a Kruppel-like transcription factor and Sp1. J. Biol. Chem. 275:8903–8910.PubMedCrossRefGoogle Scholar
  68. Zhao X, Matsumoto N, Gouon-Evans V, et al (2006) The role of Krüppel-like factor 6 (KLF6) in differentiation of embryonic stem cells into hepatocytes. Hepatology, abstract.Google Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  1. 1.Department of Genetics and Genomic SciencesMount Sinai School of MedicineNew YorkUSA

Personalised recommendations