Degradation of matrix proteins in liver fibrosis.
Hepatic fibrosis occurs as a consequence of net accumulation of matrix proteins (particularly collagen types I and III) in liver. Current concepts of the pathogenesis of liver fibrosis place major emphasis on the activation of hepatic lipocytes (fat-storing or Ito cells) to a myofibroblast-like phenotype with a consequent increase in their synthesis of matrix proteins. While this is an important factor, there is increasing evidence to indicate that liver fibrosis is a dynamic pathologic process in which altered matrix degradation may also play a significant role. Extracellular degradation of matrix proteins is regulated by a family of enzymes called the matrix metalloproteinases, which is subdivided into three groups; collagenases which degrade interstitial collagens (types I, II and III), type IV collagenases/gelatinases which degrade basement membrane (type IV) collagen and gelatins and stromelysins which degrade a broad range of substrates including proteoglycans, laminin, gelatins and fibronectin. The extracellular activity of these enzymes is regulated by several mechanisms which include alterations in gene transcription and proenzyme synthesis, cleavage of secreted proenzymes to active forms, and specific inhibition of activated forms by tissue inhibitor(s) of metalloproteinases (TIMPs). In liver, current evidence indicates that activated hepatic lipocytes and Kupffer cells play a central role in synthesis of matrix metalloproteinases. Under defined conditions they synthesize interstitial collagenase, 72 kDa and 95 kDa type IV collagenase/gelatinase and possibly stromelysin. Moreover, lipocytes also contribute to regulation of the extracellular activity of these enzymes by secretion of TIMP-1 and alpha 2-macroglobulin.(ABSTRACT TRUNCATED AT 250 WORDS)
Arthur
M J
MJ
University Medicine, University of Southampton, UK.
D000818:Animals; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006023:Glycoproteins / Q000502:physiology; D006801:Humans; D008103:Liver Cirrhosis / Q000201:enzymology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011506:Proteins / Q000502:physiology; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases
D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D011506:Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D008666:Metalloendopeptidases