Abstract
Tremendous insights into the understanding of hepatic fibrosis have taken place over the past ten years. Foremost among these is the recognition that hepatic stellate cells (formerly known as lipocytes, Ito cells, or fat-storing cells) play a central role based on their ability to undergo activation following liver injury of any cause. Stellate cell activation is a broad phenotypic response, characterized by distinct functional changes in proliferation, contractility, fibrogenesis, cytokine secretion, and matrix degradation. Insights gained into the molecular regulation of hepatic stellate cell activation will lead to new, targeted approaches to hepatic fibrosis in the future, and could lead to reduced morbidity and mortality in patients with chronic liver injury.
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References
Dufour MC, Stinson FS, Caces MF. Trends in cirrhosis morbidity and mortality: United States 1979–1988. Semin Liver Dis 1993; 13:109–125.
Rojkind M, Giambrone MA, Biempica L. Collagen types in normal and cirrhotic human liver. Gastroenterology 1979; 710–719.
Seyer JM, Huheson ET, Kang AH. Collagen polymorphism in normal and cirrhotic human liver. J Clin Invest 1979;59:241–248.
Arenson DM, Friedman SL, Bissell DM. Formation of extracellular matrix in normal liver: Lipocytes as major source of proteoglycans. Gastroenterology 1988;95:441–447.
Maher JJ, Friedman SL, Roll FJ, Bissell DM. Immunolocalization of laminin in normal rat liver and biosynthesis of laminin by hepatic lipocytes in primary culture. Gastroenterology 1988; 94:1053–1062.
Martinez Hernandez A. The hepatic extracellular matrix. II. Electron immunohistochemical studies in rats with CCl4-induced cirrhosis. Lab Invest 1985;53:166–186.
Ramadori G, Schwogler S, Veit Th., Rieder H et al. Tensascin gene expression in rat liver and rat liver cells. Virchows Arch B Cell Pathol 1991;6:145–153.
Bissell DM, Arenson DA, Maher JJ, Roll FJ. Support of hepatocytes by a laminin-rich gel; evidence for a functionally significant subendothelial matrix in normal rat liver. J Clin Invest 1987; 79:801–812.
Jarnagin WR, Rockey DC, Koteliansky VE, Wang SS, Bissell DM. Expression of variant fibronectins in wound healing: Cellular source and biological activity of the EIIIA segment in rat hepatic fibrogenesis. J Cell Biol 1994;127(6):2037–2048.
Wake K. Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around the liver sinuosoids, and vitamin-storing cells in extrahepatic organs. Int Rev Cytol 1980;66:303–353.
Hendriks HF, Blaner WS, Wennekers HM, Piantedosi R, Brouwer A, de Leeuw AM, Goodman DS, Knook DL. Distributions of retinoids, retinoid-binding proteins and relaed parameters in different types of liver cells isolated from young and old rats. Eur J Biochem 1988;171:237–244.
Blomhoff R, Green MH, Berg T, Norum KR. Transport and storage of vitamin A. Science 1990;250:399–404.
Batres RO, Olson JA. A marginal vitamin A status alters the distribution of vitamin A among parenchymal and stellate cells in rat liver. J Nutrition 1987;117:874–879.
Friedman SL, Roll FJ. Isolation of hepatic lipocytes, Kupffer cells and sinusoidal endothelial cells by density gradient centrifugation with Stractan. Anal Biochem 1987;161:207–218.
Friedman SL, Roll FJ, Boyles J, Bissell DM. Hepatic lipocytes: The principal collagen-producing cells of normal rat liver. Proc Nat Acad Sci USA 1985;82:8681–8685.
Housset C, Rockey DC, Bissell DM. Endothelin receptors in rat liver: Lipocytes as a contractile target for endothelin 1. Proc Nat Acad Sci USA 1993;90:9266–9270.
Mullhaupt B, Feren A, Fodor E, Jones A. Liver expression of epidermal growth factor RNA. Rapid increases in immediate-early phase of liver regeneration. J Biol Chem 1994;269:19667–19670.
Pinzani M, Abboud HE, Gesualdo L, Abboud SL. Regulation of macrophage colony-stimulating factor in liver fat-storing cells by peptide growth factors. Am J Physiol 1992;262:C876–881.
Marra F, Valente AJ, Pinzani M, Abboud HE. Cultured human liver fat-storing cells produce monocyte chemotactic protein-1. Regulation by proinflammatory cytokines. J Clin Invest 1993; 92:1674–1680.
Friedman SL, Arthur MJP. Activation of cultured rat hepatic lipocytes by Kupffer cell conditioned medium. Direct enhancement of matrix synthesis and stimulation of cell proliferation via induction of platelet-derived growth factor receptors. J Clin Invest 1989;84:1780–1785.
Jensen S, Ratziu V, Lalazar A, Wong L, Friedman SL. Zf9, a novel zinc finger gene induced during hepatic stellate cell activation binds “GC Box” DNA and is expressed in humans. Hepatology 1995;22:293A
Wong L, Yamasaki G, Johnson RJ, Friedman SL. Induction of beta-platelet-derived growth factor receptor in rat hepatic lipocytes during cellular activation in vivo and inculture. J Clin Invest 1994;94:1563–1569.
Pinzani M, Gesualdo L, Sabbah GM, Abboud HE. Effects of platelet-derived growth factor and other polypeptide mitogens on DNA synthesis and growth of cultured rat liver fat-storing cells. J Clin Invest 1989;84:1786–1793.
Pinzani M, Abboud HE, Aron DC. Secretion of insulin-like growth factor-I and binding proteins by rat liver fat-storing cells: Regulatory role of platelet-derived growth factor. Endocrinology, 1990;127:2343–2349.
Marra F, Grandaliano G, Valente AJ, Abboud HE. Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: Potential role in liver injury. Hepatology 1995;22(3):780–787.
Bachem MG, Meyer D, Melchior R, Sell KM, Gressner AM. Activation of rat liver perisinusoidal lipocytes by transforming growth factors derived from myofibroblastlke cells. A potential mechanism of self perpetuation in liver fibrogenesis. J Clin Invest 1992;89:19–27.
Houglum K, Bedossa P, Chojkier M. TGF-beta and collagen-alpha 1 (I) gene expression are increased in hepatic acinar zone 1 of rats with iron overload. Am J Physiol 1994;267:G908–913.
Friedman SL, Yamasaki G, Wong LS. Modulation of TGF\ receptors in rat hepatic lipocytes during the hepatic wound healing response; enhanced binding but reduced gene expression accompany cellular activation in culture and in vivo. J Biol Chem 1994;269:10551–10558.
de Bleser PJ, Jannes P, van Buul-Offers SC,et al. Insulinlike growth factor-II/mannose 6-phosphate receptor is expressed on CC14-exposed rat fat-storing cells and facilitates activation of latent transforming growth factor-beta in cocultures with sinusoidal endothelial cells. Hepatology 1995;21:1429–1437.
Rockey DC, Housset CN, Friedman SL. Activation-dependent contractility of rat hepatic lipocytes in culture and in vivo. J Clin Invest 1993;92:1795–1804.
Schmit-Graff A, Desmouliere A, Gabbiani G. Heterogeneity of myofibroblast phenotypic features: An example of fibroblastic cell plasticity. Virchows Arch B Cell Pathol 1994;425:3–24.
Rockey DC, Chung JJ. Inducible nitric oxide syntase in rat hepatic lipocytes and the effect of nitric oxide on lipocyte contractility. J Clin Invest 1995;95:1199–1206.
Kawada N, Klein H, Decker K. Eicosanoid-mediated contractility of hepatic stellate cells. Biochem J 1992;285:367–371.
Arthur MJ, Stanley A, Iredale JP, et al. Secrtion of 72kDa type IV collagenase/gelatinase by cultured human lipocytes. Analysis of gene expression, protein synthesis and proteinase activity. Biochem J 1992;287:701–707.
Iredale JP, Murphy G, Hembry RM, et al. Human hepatic lipocytes synthesize tissue inhibitor of metalloproteinases-1 Implications for regulation of matrix degradation in liver. J Clin Invest 1992;90:282–287.
Arthur MJP. Role of Ito cells in the degradation of matrix in liver. J Gastroenterol Hepatol 1995;10:557–562.
Friedman SL. The cellular basis of hepatic fibrosis. New Eng1 J Med 1993;328:1828–1835.
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Friedman, S.L. Molecular mechanisms of hepatic fibrosis and principles of therapy. J Gastroenterol 32, 424–430 (1997). https://doi.org/10.1007/BF02934504
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DOI: https://doi.org/10.1007/BF02934504