insulin like growth factor binding proteins


Summary: A family of soluble proteins that bind insulin-like growth factors and modulate their biological actions at the cellular level. (Int J Gynaecol Obstet 1992;39(1):3-9)

Top Publications

  1. Santiago C, Voge J, Aad P, Allen D, Stein D, Malayer J, et al. Pregnancy-associated plasma protein-A and insulin-like growth factor binding protein mRNAs in granulosa cells of dominant and subordinate follicles of preovulatory cattle. Domest Anim Endocrinol. 2005;28:46-63 pubmed
  2. Suzuki H, Igarashi S, Nojima M, Maruyama R, Yamamoto E, Kai M, et al. IGFBP7 is a p53-responsive gene specifically silenced in colorectal cancer with CpG island methylator phenotype. Carcinogenesis. 2010;31:342-9 pubmed publisher
    ..Thus, epigenetic inactivation of IGFBP7 appears to play a key role in tumorigenesis of CRCs with CIMP by enabling escape from p53-induced senescence. ..
  3. Ye F, Chen Y, Knösel T, Schluns K, Pacyna Gengelbach M, Deutschmann N, et al. Decreased expression of insulin-like growth factor binding protein 7 in human colorectal carcinoma is related to DNA methylation. J Cancer Res Clin Oncol. 2007;133:305-14 pubmed
    ..DNA methylation is a mechanism responsible for IGFBP-7 gene silencing providing a target for therapeutic intervention of this tumor suppressor gene. ..
  4. Ma Y, Lu B, Ruan W, Wang H, Lin J, Hu H, et al. Tumor suppressor gene insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) induces senescence-like growth arrest in colorectal cancer cells. Exp Mol Pathol. 2008;85:141-5 pubmed publisher
    ..Restoration of IGFBP-rP1 function might have potential therapeutic significance in colorectal cancer. ..
  5. Cichowski K, Hahn W. Unexpected pieces to the senescence puzzle. Cell. 2008;133:958-61 pubmed publisher
    ..2008; Kuilman et al., 2008; Wajapeyee et al., 2008). These new studies identify unanticipated contributors to this tumor-suppressing cell state. ..
  6. Walker G, MacLeod K, Williams A, Cameron D, Smyth J, Langdon S. Insulin-like growth factor binding proteins IGFBP3, IGFBP4, and IGFBP5 predict endocrine responsiveness in patients with ovarian cancer. Clin Cancer Res. 2007;13:1438-44 pubmed
    ..These results indicate that expression levels of certain IGFBP family members in ovarian cancers are estrogen regulated and can, thus, help identify patients who could benefit from endocrine therapy. ..
  7. Lin J, Lai M, Huang Q, Ma Y, Cui J, Ruan W. Methylation patterns of IGFBP7 in colon cancer cell lines are associated with levels of gene expression. J Pathol. 2007;212:83-90 pubmed
    ..Our study is the first to provide detailed methylation profiles of the IGFBP7 5' CpG island and shows that hypermethylation of the CpG island in exon 1 of IGFBP7 is closely related to the absence of its expression in colon cancer cells. ..
  8. Davies S, Watkins G, Mansel R, Jiang W. Differential expression and prognostic implications of the CCN family members WISP-1, WISP-2, and WISP-3 in human breast cancer. Ann Surg Oncol. 2007;14:1909-18 pubmed
    ..WISPs may play important but contrasting roles in breast cancer. WISP-1 seems to act as a tumor suppressor and WISP-2 as a factor that stimulates aggressiveness; WISP-3 has no definable beneficial or detrimental role. ..
  9. Sato Y, Chen Z, Miyazaki K. Strong suppression of tumor growth by insulin-like growth factor-binding protein-related protein 1/tumor-derived cell adhesion factor/mac25. Cancer Sci. 2007;98:1055-63 pubmed
    ..Cell surface IGFBP-rP1 may reduce the anchorage-independent growth ability, leading to the marked loss of tumorigenicity. ..

More Information


  1. Jiang W, Xiang C, Cazacu S, Brodie C, Mikkelsen T. Insulin-like growth factor binding protein 7 mediates glioma cell growth and migration. Neoplasia. 2008;10:1335-42 pubmed
    ..These two factors together suggest that IGFBP-7 can regulate glioma cell migration through the AKT-ERK pathway, thereby playing an important role in glioma growth and migration. ..
  2. Shynlova O, Tsui P, Dorogin A, Langille B, Lye S. Insulin-like growth factors and their binding proteins define specific phases of myometrial differentiation during pregnancy in the rat. Biol Reprod. 2007;76:571-8 pubmed
    ..Igfbp5 gene was induced during postpartum involution. Our results suggest the importance of the IGF system in phenotypic and functional changes of myometrial SMCs throughout gestation in preparation for labor. ..
  3. Chen Y, Pacyna Gengelbach M, Ye F, Knösel T, Lund P, Deutschmann N, et al. Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) has potential tumour-suppressive activity in human lung cancer. J Pathol. 2007;211:431-8 pubmed
    ..The data suggest that IGFBP-rP1 is a tumour suppressor inactivated by DNA methylation in human lung cancer. ..
  4. Ruan W, Xu E, Xu F, Ma Y, Deng H, Huang Q, et al. IGFBP7 plays a potential tumor suppressor role in colorectal carcinogenesis. Cancer Biol Ther. 2007;6:354-9 pubmed
    ..Based on above results, we conclude that IGFBP7 plays a potential tumor suppressor role in colorectal carcinogenesis. ..
  5. Zeggini E, Weedon M, Lindgren C, Frayling T, Elliott K, Lango H, et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science. 2007;316:1336-41 pubmed
    ..The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes. ..
  6. Kleer C, Zhang Y, Merajver S. CCN6 (WISP3) as a new regulator of the epithelial phenotype in breast cancer. Cells Tissues Organs. 2007;185:95-9 pubmed
    ..This review will focus on the current knowledge regarding the function of CCN6 in breast cancer with special emphasis on the emerging role of CCN6 as a regulator of the epithelial phenotype and E-cadherin expression in the breast. ..
  7. Arquier N, Geminard C, Bourouis M, Jarretou G, Honegger B, Paix A, et al. Drosophila ALS regulates growth and metabolism through functional interaction with insulin-like peptides. Cell Metab. 2008;7:333-8 pubmed publisher
    ..These results lead us to propose an evolutionary perspective in which ALS function appeared prior to the separation between metabolic and growth effects that are associated with vertebrate insulin and IGFs. ..
  8. Sierra Johnson J, Romero Corral A, Somers V, Lopez Jimenez F, Malarstig A, Brismar K, et al. IGF-I/IGFBP-3 ratio: a mechanistic insight into the metabolic syndrome. Clin Sci (Lond). 2009;116:507-12 pubmed publisher
    ..01). In conclusion, the IGF-I/IGFBP-3 ratio is significantly associated with the metabolic syndrome. Calculating the ratio of these two proteins may provide insight into the metabolic syndrome clustering phenomenon. ..
  9. Salehi Z, Mashayekhi F, Naji M. Insulin like growth factor-1 and insulin like growth factor binding proteins in the cerebrospinal fluid and serum from patients with Alzheimer's disease. Biofactors. 2008;33:99-106 pubmed
    ..and other physiological fluids are associated with a group of high-affinity binding proteins insulin like growth factor binding proteins (IGFBPs) that specifically bind and modulate their bioactivity at the cellular level...
  10. Kutsukake M, Ishihara R, Yoshie M, Kogo H, Tamura K. Involvement of insulin-like growth factor-binding protein-related protein 1 in decidualization of human endometrial stromal cells. Mol Hum Reprod. 2007;13:737-43 pubmed
    ..These results suggest that IGFBP-rP1 may play a role in decidualization of ESCs. ..
  11. Subramanian A, Sharma A, Banerjee D, Jiang W, Mokbel K. Evidence for a tumour suppressive function of IGF1-binding proteins in human breast cancer. Anticancer Res. 2007;27:3513-8 pubmed
    ..030). For IGFBP-7 mRNA, both TNM 1 (p=0.0077) and TNM 2 (p=0.015) had significantly more expression than TNM 3 samples. This study supports the role of IGFBP-1, -3 and -7 as potential tumour suppressor genes in human breast cancer. ..
  12. Tamura K, Hashimoto K, Suzuki K, Yoshie M, Kutsukake M, Sakurai T. Insulin-like growth factor binding protein-7 (IGFBP7) blocks vascular endothelial cell growth factor (VEGF)-induced angiogenesis in human vascular endothelial cells. Eur J Pharmacol. 2009;610:61-7 pubmed publisher
    ..These findings indicate that IGFBP7 can modulate the stimulatory effect of VEGF on angiogenesis by interfering with VEGF expression as well as VEGF signaling and not by inducing apoptosis. ..
  13. Wajapeyee N, Serra R, Zhu X, Mahalingam M, Green M. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell. 2008;132:363-74 pubmed publisher
    ..Immunohistochemical analysis of human skin, nevi, and melanoma samples implicates loss of IGFBP7 expression as a critical step in melanoma genesis...
  14. Lin J, Lai M, Huang Q, Ruan W, Ma Y, Cui J. Reactivation of IGFBP7 by DNA demethylation inhibits human colon cancer cell growth in vitro. Cancer Biol Ther. 2008;7:1896-900 pubmed
    ..These data suggest that 5-aza-dC has clinical potential in the treatment of colorectal cancer. ..
  15. Tamimi R, Cox D, Kraft P, Pollak M, Haiman C, Cheng I, et al. Common genetic variation in IGF1, IGFBP-1, and IGFBP-3 in relation to mammographic density: a cross-sectional study. Breast Cancer Res. 2007;9:R18 pubmed
    ..2% (p for trend = 0.0004). Permutation testing demonstrated that results as strong as these are unlikely to occur by chance (p = 0.0005). Common genetic variation in IGF1 is strongly associated with percentage mammographic density. ..
  16. Grønbaek H, Flyvbjerg A, Mellemkjaer L, Tjønneland A, Christensen J, Sørensen H, et al. Serum insulin-like growth factors, insulin-like growth factor binding proteins, and breast cancer risk in postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2004;13:1759-64 pubmed
    ..Serum IGFBP-3 and IGF-II levels were positively associated with ER-positive breast cancer risk. This may suggest an important relationship among IGFs, IGFBPs, the ER system, and breast cancer development in postmenopausal women. ..
  17. Ruan W, Lin J, Xu E, Xu F, Ma Y, Deng H, et al. IGFBP7 plays a potential tumor suppressor role against colorectal carcinogenesis with its expression associated with DNA hypomethylation of exon 1. J Zhejiang Univ Sci B. 2006;7:929-32 pubmed
    ..In conclusion, our study clearly demonstrated that IGFBP7 plays a potential tumor suppressor role against colorectal carcinogenesis and its expression is associated with DNA hypomethylation of exon 1. ..
  18. Kubota S, Kawaki H, Kondo S, Yosimichi G, Minato M, Nishida T, et al. Multiple activation of mitogen-activated protein kinases by purified independent CCN2 modules in vascular endothelial cells and chondrocytes in culture. Biochimie. 2006;88:1973-81 pubmed
  19. Lopez Bermejo A, Khosravi J, Fernandez Real J, Hwa V, Pratt K, Casamitjana R, et al. Insulin resistance is associated with increased serum concentration of IGF-binding protein-related protein 1 (IGFBP-rP1/MAC25). Diabetes. 2006;55:2333-9 pubmed
    ..These findings show for the first time that circulating IGFBP-rP1 is increased with insulin resistance, and they also suggest novel interactions between IGFBP-rP1 and the IGF system in humans. ..
  20. Siwanowicz I, Popowicz G, Wisniewska M, Huber R, Kuenkele K, Lang K, et al. Structural basis for the regulation of insulin-like growth factors by IGF binding proteins. Structure. 2005;13:155-67 pubmed
    ..Although CBP-4 does not bind individually to either IGF-I or NBP-4, in the ternary complex, CBP-4 contacts both and also blocks the IGF-IR binding region of IGF-I. ..
  21. Cheung C, Vesey D, Cotterill A, Douglas M, Gobe G, Nicol D, et al. Altered messenger RNA and protein expressions for insulin-like growth factor family members in clear cell and papillary renal cell carcinomas. Int J Urol. 2005;12:17-28 pubmed
    ..This altered expression is differentially regulated according to the histologic subtype of RCC, and suggests that the IGF/IGFBP axis may play an important role in determining the malignant phenotype of RCC. ..
  22. Fletcher O, Gibson L, Johnson N, Altmann D, Holly J, Ashworth A, et al. Polymorphisms and circulating levels in the insulin-like growth factor system and risk of breast cancer: a systematic review. Cancer Epidemiol Biomarkers Prev. 2005;14:2-19 pubmed
    ..Further large studies, or combined analysis of data from existing studies, are needed to quantify these effects more precisely. ..
  23. Davis L, Chen Y, Sen M. WISP-3 functions as a ligand and promotes superoxide dismutase activity. Biochem Biophys Res Commun. 2006;342:259-65 pubmed
    ..Furthermore, apart from regulating collagen II and aggrecan expression, WISP-3 may also promote superoxide dismutase expression and activity in chondrocytes. ..
  24. Grotendorst G, Duncan M. Individual domains of connective tissue growth factor regulate fibroblast proliferation and myofibroblast differentiation. FASEB J. 2005;19:729-38 pubmed
    ..These data provide a molecular basis for the divergence of CTGF actions on connective tissue cell types and suggest a model for functional analysis of all of the CCN family gene products. ..
  25. Brigstock D, Lau L, Perbal B. Report and abstracts of the 3rd International Workshop on the CCN Family of Genes. St Malo, France, 20-23 October 2004. J Clin Pathol. 2005;58:463-78 pubmed
  26. Matilainen M, Malinen M, Saavalainen K, Carlberg C. Regulation of multiple insulin-like growth factor binding protein genes by 1alpha,25-dihydroxyvitamin D3. Nucleic Acids Res. 2005;33:5521-32 pubmed
    ..In conclusion, IGFBP1, 3 and 5 are primary 1alpha,25(OH)2D3 target genes that in intact cells are each under the control of multiple VDREs. ..
  27. Burger A, Leyland Jones B, Banerjee K, Spyropoulos D, Seth A. Essential roles of IGFBP-3 and IGFBP-rP1 in breast cancer. Eur J Cancer. 2005;41:1515-27 pubmed
    ..In this review, we have examined the roles of IGFBP-3 and IGFBP-rP1 in breast cancer, and discuss the potential impact of these two proteins in mammary carcinoma risk assessment and the development of treatments for breast cancer. ..
  28. Heald A, Kaushal K, Anderson S, Redpath M, Durrington P, Selby P, et al. Effects of hormone replacement therapy on insulin-like growth factor (IGF)-I, IGF-II and IGF binding protein (IGFBP)-1 to IGFBP-4: implications for cardiovascular risk. Gynecol Endocrinol. 2005;20:176-82 pubmed
    ..The effect of progestogens on IGF bioavailability could be an important determinant of the longer-term risks of specific HRT preparations by opposing the potentially beneficial effects of CEE alone on cardiovascular risk. ..
  29. Fang P, Hwa V, Rosenfeld R. IGFBPs and cancer. Novartis Found Symp. 2004;262:215-30; discussion 230-4, 265-8 pubmed
    ..Further studies are necessary to demonstrate whether the ability of IGFBPs to inhibit the proliferation of cancer cells under in vitro conditions has significant clinical implications. ..
  30. Schernhammer E, Holly J, Pollak M, Hankinson S. Circulating levels of insulin-like growth factors, their binding proteins, and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2005;14:699-704 pubmed
    ..IGFBP-3, IGFBP-1, and free IGF are not associated with breast cancer risk in either premenopausal or postmenopausal women in this cohort. ..
  31. Fleming J, Leibowitz B, Kerr D, Cohick W. IGF-I differentially regulates IGF-binding protein expression in primary mammary fibroblasts and epithelial cells. J Endocrinol. 2005;186:165-78 pubmed
  32. Lamb R, Thomson W, Ogilvie E, Donn R. Wnt-1-inducible signaling pathway protein 3 and susceptibility to juvenile idiopathic arthritis. Arthritis Rheum. 2005;52:3548-53 pubmed
    ..Association and replication of a polymorphism within the first intron of the WISP3 gene have been shown in patients with polyarticular-course JIA. The functional significance of the WISP3*G84A SNP is being determined. ..
  33. Canzian F, McKay J, Cleveland R, Dossus L, Biessy C, Rinaldi S, et al. Polymorphisms of genes coding for insulin-like growth factor 1 and its major binding proteins, circulating levels of IGF-I and IGFBP-3 and breast cancer risk: results from the EPIC study. Br J Cancer. 2006;94:299-307 pubmed
    ..Common genetic variation in these candidate genes does not play a major role in altering breast cancer risk in Caucasians. ..
  34. Paye J, Forsten Williams K. Regulation of insulin-like growth factor-I (IGF-I) delivery by IGF binding proteins and receptors. Ann Biomed Eng. 2006;34:618-32 pubmed
  35. Greenstein J, Guest S, Tan J, Tummala P, Busque S, Rabkin R. Circulating growth hormone binding protein levels and mononuclear cell growth hormone receptor expression in uremia. J Ren Nutr. 2006;16:141-9 pubmed
  36. Schutze N, Schenk R, Fiedler J, Mattes T, Jakob F, Brenner R. CYR61/CCN1 and WISP3/CCN6 are chemoattractive ligands for human multipotent mesenchymal stroma cells. BMC Cell Biol. 2007;8:45 pubmed
    ..This may be relevant for their possible role in connective tissue repair. ..
  37. Olausson H, Lof M, Brismar K, Lewitt M, Forsum E, Sohlstrom A. Longitudinal study of the maternal insulin-like growth factor system before, during and after pregnancy in relation to fetal and infant weight. Horm Res. 2008;69:99-106 pubmed
    ..43 to -0.59) with IGFBP-1 at gestational week 20 (p = 0.041), 32 (p = 0.012) and 35 (p = 0.003). We propose there is a finely tuned balance among the components of the IGF system, providing a means for fetal growth regulation. ..
  38. Cudrici C, Ito T, Zafranskaia E, Weerth S, Rus V, Chen H, et al. Complement C5 regulates the expression of insulin-like growth factor binding proteins in chronic experimental allergic encephalomyelitis. J Neuroimmunol. 2008;203:94-103 pubmed publisher
    ..The dysregulation of these genes suggests that these proteins might be responsible for the gliosis and lack of remyelination seen in C5-d mice with chronic EAE. ..
  39. Sullivan T, Micke G, Magalhaes R, Phillips N, Perry V. Dietary protein during gestation affects placental development in heifers. Theriogenology. 2009;72:427-38 pubmed publisher
    ..28 to-0.33). The number of uterine caruncles in the nonpregnant adult offspring did not correlate with the dam's genotype, nutrition treatment, or cotyledon number in the expelled placenta. ..
  40. Gai Y, Wang L, Song L, Zhao J, Qiu L, Xing K. A putative endocrine factor SIBD (single insulin binding domain protein) involved in immune response of Chinese mitten crab Eriocheir sinensis. Fish Shellfish Immunol. 2010;28:10-7 pubmed publisher
    ..anguillarum stimulation collectively implied that EsSIBD was probably involved in endocrine and immune systems of Chinese mitten crab, and provided insight into the cross-talk between the invertebrate endocrine and immune system. ..
  41. Nunez N, Hursting S, Yakar S, Fowler D, Vinson C. Obesity provides a permissive milieu in inflammation-associated carcinogenesis: analysis of insulin and IGF pathways. Methods Mol Biol. 2009;512:29-37 pubmed publisher
    ..Therefore, we postulate that the pathways associated with insulin resistance and inflammation, rather than adipocyte-derived factors, may represent key prevention or therapeutic targets for disrupting the obesity-cancer link. ..
  42. Liu M, Stevens Lapsley J, Jayaraman A, Ye F, Conover C, Walter G, et al. Impact of treadmill locomotor training on skeletal muscle IGF1 and myogenic regulatory factors in spinal cord injured rats. Eur J Appl Physiol. 2010;109:709-20 pubmed publisher
    ..Training-induced muscle regeneration and fiber hypertrophy following SCI was associated with an increase in IGF1, an increase in Pax7 positive nuclei, and upregulation of MRFs. ..
  43. Mihelčić M, Simic G, Babić Leko M, Lavrac N, Dzeroski S, Smuc T. Using redescription mining to relate clinical and biological characteristics of cognitively impaired and Alzheimer's disease patients. PLoS ONE. 2017;12:e0187364 pubmed publisher
    ..Therefore, further studies should investigate the role of PAPP-A in the development of AD more thoroughly...
  44. Eliakim A, Nemet D. Exercise training, physical fitness and the growth hormone-insulin-like growth factor-1 axis and cytokine balance. Med Sport Sci. 2010;55:128-40 pubmed publisher
    ..Finally, changes in the balance of anabolic and catabolic hormones and inflammatory mediators during the training season may help elite athletes and their coaches in their training and preparation for competition. ..
  45. Van der Kaay D, Hendriks A, Ester W, Leunissen R, Willemsen R, de Kort S, et al. Genetic and epigenetic variability in the gene for IGFBP-3 (IGFBP3): correlation with serum IGFBP-3 levels and growth in short children born small for gestational age. Growth Horm IGF Res. 2009;19:198-205 pubmed publisher
    ..Polymorphic variation in the IGFBP3 promoter region is correlated with IGFBP-3 levels, spontaneous growth and response to GH treatment in short SGA children. ..
  46. Narayanaswamy V, Rettig K, Bhowmick S. Excessive growth. Clin Pediatr (Phila). 2008;47:705-8 pubmed publisher
    ..The nature of pituitary adenoma and treatment options in children with this condition have also been discussed. ..
  47. Malik J, Stulc T, Wichterle D, Melenovsky V, Chytilova E, Lacinova Z, et al. Hyperlipidemia is associated with altered levels of insulin-like growth factor-I. Physiol Res. 2008;57:919-25 pubmed
    ..The mechanism is presumably different in IHC and MHL. Because of prominent reduction of IGFBP-3 in patients with MHL, they have reduced total IGF-I despite the actual elevation IGF-I/IGFBP-3 ratio as a surrogate of free IGF-I. ..
  48. Dayton W, White M. Cellular and molecular regulation of muscle growth and development in meat animals. J Anim Sci. 2008;86:E217-25 pubmed
    ..Consequently, this review will focus on the roles of IGF-I and IGFBP in the cellular and molecular mechanisms of action of anabolic steroids and TGF-beta and myostatin, respectively. ..
  49. Parker E, Hegde A, Buckley M, Barnes K, Baron J, Nilsson O. Spatial and temporal regulation of GH-IGF-related gene expression in growth plate cartilage. J Endocrinol. 2007;194:31-40 pubmed
    ..In addition, the decrease in growth velocity that occurs with age may be caused, in part, by decreasing expression of IGF-II and increasing expression of type 2 IGF receptor and multiple IGFBPs. ..
  50. Fridman A, Rosati R, Li Q, Tainsky M. Epigenetic and functional analysis of IGFBP3 and IGFBPrP1 in cellular immortalization. Biochem Biophys Res Commun. 2007;357:785-91 pubmed
    ..Analysis of how IGFBPs regulate immortalization will lead to a better understanding of this process and may lead to novel methods for the prevention and treatment of cancer. ..
  51. Lee K, Cobb L, Paharkova Vatchkova V, Liu B, Milbrandt J, Cohen P. Contribution of the orphan nuclear receptor Nur77 to the apoptotic action of IGFBP-3. Carcinogenesis. 2007;28:1653-8 pubmed
    ..Taken together, our results verify an important role for the orphan nuclear receptor Nur77 in the apoptotic actions of IGFBP-3. ..
  52. Burchardt P, Gozdzicka Jozefiak A, Siminiak T. [IGF-1--a new risk factor for coronary atherosclerosis]. Kardiol Pol. 2006;64:1297-302 pubmed
  53. Ueki M, Koda M, Yamamoto S, Matsunaga Y, Murawaki Y. Preventive and therapeutic effects of angiotensin II type 1 receptor blocker on hepatic fibrosis induced by bile duct ligation in rats. J Gastroenterol. 2006;41:996-1004 pubmed
    ..Candesartan attenuated liver fibrosis via suppression of collagen I and TGF-beta1 expression, HSC activation, and lipid peroxidation protein, showing its preventive and therapeutic effects on cholestasis-induced liver fibrosis. ..