A cascade-mechanism of fat storing cell activation forms the basis of the fibrogenic reaction of the liver.
Evidence has been provided that fat storing cells (FSC) are the major source of extracellular matrix components (ECM), if these precursor cells are activated in areas of necroinflammation to proliferate and to switch from the retinoid storing to the ECM-producing phenotype termed myofibroblast (MFB). The mechanisms of FSC activation, which are crucial to fibrogenesis, have been studied under cell culture conditions. FSC are strongly activated by cytokines from Kupffer cells (KC) and platelets, of which TGF-beta is of great importance. It stimulates ECM gene expression but inhibits FSC proliferation and stimulates phenotypic transformation. It is activated in cooperation with endothelial cells. TGF-alpha, also secreted by KC, stimulates FSC proliferation. In addition, hepatocytes (PC) also stimulate proliferation of FSC but ECM production is not affected. The mitogenic effect is mediated by TGF-alpha, IGF-1 and other cytokines. The paracrine signals of PC are increased by PC damage. During transformation MFB increasingly express TGF-beta and TGF-alpha, which are involved in autocrine stimulation of myofibroblasts and paracrine activation of still untransformed FSC. Cellular crosstalk let us suggest a three-step cascade model of FSC activation. A preinflammatory phase initiates FSC activation by discharge of mitogenic cytokines (TGF-alpha, IGF-1) from damaged PC followed by the inflammatory phase based on cytokines (TGF-beta etc.) from activated KC. In the post-inflammatory phase MFB are stimulated by autocrine mechanisms contributing potentially to a perpetuation of the fibrogenic process even after cessation of the primary event (PC damage).
Gressner
A M
AM
Department of Clinical Chemistry, Philipps University, Marburg, Germany.
Chunfang
G
G
D017667:Adipocytes / Q000473:pathology / Q000502:physiology*; D000818:Animals; D002455:Cell Division; D016207:Cytokines / Q000096:biosynthesis; D004727:Endothelium / Q000502:physiology; D005109:Extracellular Matrix / Q000473:pathology / Q000502:physiology; D006801:Humans; D007249:Inflammation; D007728:Kupffer Cells / Q000502:physiology; D008099:Liver / Q000473:pathology* / Q000502:physiology*; D008103:Liver Cirrhosis / Q000473:pathology* / Q000503:physiopathology*; D008954:Models, Biological; D010641:Phenotype; D011509:Proteoglycans / Q000096:biosynthesis
D016207:Cytokines; D011509:Proteoglycans