Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0239946 (liver fibrosis)
 8,268 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In conditions of chronic liver inflammation, liver fat-storing cells (FSC) differentiate into 'myofibroblast-like cells'. This transition is characterized by a gradual loss of vitamin A stores, and previous studies suggest a possible relationship between the intracellular retinoid content and the proliferative potential of this cell type. In the present study, we further characterized this aspect of FSC biology by monitoring ultrastructural changes and growth characteristics during several serial passages in culture. Our observations suggest that the complete transition to the 'myofibroblast-like phenotype' is paralleled by a sudden and remarkable increase in the growth rate. At this stage, cell growth appears rather independent from the presence of mitogens in the culture medium, suggesting cell transformation. Accordingly, the mitogenic effects of platelet-derived growth factor and epidermal growth factor appears reduced when compared to those observed in FSC retaining the original 'storing' phenotype. Incubation of vitamin A-depleted FSC with retinol and retinoic acid resulted in the partial recovery of intracellular retinoid stores and in a significant reduction of basal growth rate and basal and growth factor-induced DNA synthesis. In summary, these in vitro observations suggest that intracellular retinoids play a central role in the control of unstimulated and growth factor-induced FSC proliferation and may help understand in vivo mechanisms leading to liver fibrosis.
 ...
PMID:Phenotypical modulation of liver fat-storing cells by retinoids. Influence on unstimulated and growth factor-induced cell proliferation. 150 Jun 85

The inability of the 'ethanol/high vitamin A Lieber-DeCarli diet' to induce liver fibrosis in two different rat strains was further evaluated by determining changes in parameters of liver cell damage and of retinoid and lipid metabolism. In the ethanol/vitamin A-treated group, slight but constant hepatic cell damage, as indicated by elevated alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase activities in blood, was already observed at 6 months and maintained until the time of death at 16 months. Serum gamma-glutamyl transaminase activities were not raised. Moderate parenchymal liver cell damage was not accompanied by fibrosis. Hypertriglyceridemia or hypercholesterolemia were observed at 6-16 months of chronic alcohol administration. This response was strain dependent. In ethanol-treated rats of both strains, total liver retinoids and serum retinol concentrations were not altered. Therefore, the hypothesis that interaction between alcohol and retinoids is a major factor in the pathogenesis of alcoholic liver disease, needs to be reconsidered.
 ...
PMID:Chronic administration of ethanol with high vitamin A supplementation in a liquid diet to rats does not cause liver fibrosis. 2. Biochemical observations. 174 28

In mammals, liver perisinusoidal stellate cells play an important role as a main store of body retinol (vitamin A). This fat-soluble vitamin is essential for vision, and regulates differentiation and growth of many cell types during embryonal development as well as in adult tissues. Thus, many cell types require a continuous supply of retinol. The storage of retinol (as retinyl esters) in stellate cells ascertains ample access of retinol to such cells also during periods with a low dietary intake. In lower vertebrates such as fish, vitamin A-storing stellate cells are found not only in the hepatic lobule, but also in the connective tissues of organs like intestine, kidney, ovaries, testes, and gills. Extrahepatic vitamin A-storing stellate cells are found in higher vertebrates when excessive doses of vitamin A are administered. It is not clear at present whether these cells also play a role in retinol metabolism under normal conditions. Stellate cells proliferate in a fibrotic liver, and they have been found to synthesize connective tissue compounds such as collagen. It was recently demonstrated that stellate cells are the principal cellular source of collagen and other extracellular substances in normal as well as fibrotic livers. Therefore, stellate cells, which seem to be a specialized type of pericyte, have a central role in the pathological changes observed during the development of liver fibrosis.
 ...
PMID:Perisinusoidal stellate cells of the liver: important roles in retinol metabolism and fibrosis. 200 86

Male F-344 rats were treated for 10 weeks either with CCl4 (0.2 ml/kg, per os, twice a week) or with CCl4 (same as above) and phenobarbital (0.2 g/l in drinking water). Liver fibrosis and cirrhosis developed in both treated groups, and was confirmed histologically. Cirrhosis was more frequent after the CCl4 + phenobarbital treatment. The collagen content of the liver, measured by morphometry and biochemically, was significantly higher in the animals of the group treated with CCl4 + phenobarbital than in the animals treated only with CCl4. Specially altered fat-storing cells (Ito cells) were found in the periportal and septal fibrotic areas in direct proportion to the amount of fibrosis and cirrhosis. They were identified as altered fat-storing cells by their desmin content and Vitamin A storing capability. This study demonstrated that these cells were enlarged and contained neutral fat, lipofuscin and PAS-positive material. The potential role of GAG-containing FSC in fibrogenesis is discussed.
 ...
PMID:Glycosaminoglycan containing fat-storing cells in hepatic fibrogenesis. 315 42

Primary cultures and cell lines were established from suspensions of purified fat-storing cells isolated from the rat liver. When seeded at a suitable density, fat-storing cells in primary culture reached confluency in 3 to 4 days and could be transferred and established as cell lines for at least two passages. The typical morphological characteristics of fat-storing cells in vivo were retained in the cells during primary culture. Vitamin A fluorescence was still associated with lipid droplets of cells in culture up to and including the second passage. Investigation of the cytoskeletal structure by indirect immunofluorescence showed the presence of vimentin, actin and tubulin in the cells; no alpha-prekeratin was present. The presence of vimentin suggested a fibroblastic or possible myogenic origin for fat-storing cells. The presence of connective tissue components in fat-storing cells in culture was demonstrated by indirect immunofluorescence. Collagen Types I and IV and laminin were present intracellularly in small granules in fat-storing cells in primary culture and in the first passage. Cells in the fourth passage contained only collagen Type 1. Fibronectin was only aligned extracellularly along the cell membrane, which did not exclude an extracellular source. Rat liver fat-storing cells in culture show a high proliferating capacity. Cell multiplication during prolonged culture was associated with phenotypic transition to a more fibroblastic appearance and gradual disappearance of vitamin A. These results indicate that fat-storing cells may be among the cell types involved in pathological changes observed during development of liver fibrosis.
 ...
PMID:Purified rat liver fat-storing cells in culture divide and contain collagen. 637 50

We previously observed that a retinoid analog can protect against liver parenchymal damage and liver fibrosis, whereas it accelerates liver fibrosis which is not accompanied by any parenchymal damage. To elucidate these conflicting effects, we examined the effects of retinoid in 3T3 L1 preadipocytes as a model of liver stellate cells. Retinoids, including all-trans retinol, all-trans and 9-cis retinoic acids, enhanced the cell growth and the expression of the type I procollagen gene as well as its peptide synthesis, while reducing collagenase activities. Although no retinoid enhanced the transforming growth factor (TGF)-beta 1 mRNA, retinoids may stimulate collagen production through activating TGF-beta, as was recently reported. These results help explain the observation in the liver fibrosis model with no parenchymal damage. In contrast, we also found that interferon (IFN) alpha beta and gamma inhibited cell growth and down-regulated markedly type I procollagen as well as TGF-beta 1 mRNA, suggesting that they suppress by acting directly on extracellular matrix-producing cells.
 ...
PMID:Modulation of collagen synthesis and degradation by retinoids and cytokines in 3T3 L1 preadipocytes. 752 59

Earlier studies have shown that retinoid administration suppresses the generation of hepatic fibrosis and stimulates its regression in normal (i.e., vitamin A-sufficient) carbon tetrachloride-treated rats. This study focuses on the possible role of a marginal or deficient vitamin A status on carbon tetrachloride-induced fibrosis. This experimental study in rats shows that vitamin A status, reflected by hepatic retinoid content (retinol and retinyl esters), modulates the development of hepatic fibrosis induced by carbon tetrachloride. In rats with low hepatic retinoid levels (12 +/- 0.9 micrograms/gm liver), carbon tetrachloride-induced liver fibrosis was more pronounced than in rats with sufficient hepatic retinoid levels (1,065 +/- 327 micrograms/gm liver). Enhanced liver fibrogenesis was confirmed both morphologically and by a higher hydroxyproline content of the liver. It was associated with a reduced liver weight and the development of parenchymal regeneration nodules. Furthermore, carbon tetrachloride treatment itself reduced the hepatic retinoid content in rats independently of the liver vitamin A status before treatment and increased serum retinol levels in vitamin A-sufficient rats. The results show that the vitamin A status of the liver plays an important role in hepatic fibrogenesis. Low hepatic vitamin A levels, which can be the result not only of low dietary intake but also of interference with vitamin A metabolism by agents such as ethanol and carbon tetrachloride, may be a risk factor for the development of liver fibrosis. We suggest that retinoids modulate collagen synthesis and deposition irrespective of the degree of hepatocellular necrosis induced by carbon tetrachloride.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Vitamin A deficiency potentiates carbon tetrachloride-induced liver fibrosis in rats. 827 55

Hepatic stellate cells (vitamin A-storing cells, lipocytes, fat-storing cells, Ito cells) exist in the perisinusoidal space of the hepatic lobule, and store 80% of retinoids in the whole body as retinyl palmitate in lipid droplets in the cytoplasm. In physiological conditions, these cells play pivotal roles in the regulation of retinoid homeostasis; they express specific receptors for retinol-binding protein (RBP), a binding protein specific for retinol, on their cell surface, and take up the complex of retinol and RBP by receptor-mediated endocytosis. By contrast, in pathological conditions such as liver fibrosis, these cells lose retinoids, and synthesize a large amount of extracellular matrix (ECM) components including collagen, proteoglycan and adhesive glycoproteins. The morphology of these cells also changes from the star-shaped stellate cells to that of fibroblasts or myofibroblasts. It is concluded that three-dimensional structure of the ECM components reversibly regulates the morphology, proliferation, and functions of the hepatic stellate cells.
 ...
PMID:Hepatic stellate cells--from the viewpoint of retinoid handling and function of the extracellular matrix. 915 61

Hepatic stellate cell (also referred to as Ito cell, fat-storing cell, perisinusoidal cell, lipocyte) is one of the sinusoid-constituent cells that play multiple roles in liver pathophysiology. Although identification of the stellate cell had taken about 100 years because of the misconception caused by the discoverer von Kupffer, Wake made a great contribution to the "re" discovery of the cell in 1971. Establishment of the isolation of hepatic non-parenchymal cells from rats by Knook has made it possible to uncover the metabolic function of individual cells. Now, the stellate cell function is expanding from a retinol (fat)-storing site to a center of extracellular matrix metabolism and mediator production in the liver. Function as a liver specific pericyte has also been elucidated. Transition of the stellate cells from the vitamin A-storing phenotype to "activated" or "myofibroblastic" cells that produce a large amount of type I collagen and transforming growth factor beta triggers the progress of liver fibrosis in the course of hepatic inflammation. Communication of the stellate cells with the other hepatic constituent cells and invading inflammatory cells is also an important factor that regulates the local pathological reaction. Analysis of cellular and molecular aspects of the stellate cell activation would lead to the establishment of a novel therapeutic strategy against the progress of liver fibrosis in human liver disease.
 ...
PMID:The hepatic perisinusoidal stellate cell. 930 68

Liver stellate cells (SCs) play central roles in both the storage of retinol and the development of liver fibrosis. The present study is aimed to understand the mechanism by which retinoic acid (RA, an active metabolite of retinol) enhances hepatic fibrosis in rats. We tested the effect of 9-cis-RA on several aspects in vitro rat SC cultures, including the activity of cellular plasminogen activator (PA), messenger RNA (mRNA), and protein levels of transforming growth factor-beta (TGF-beta) mRNA level of type-I procollagen, and the activity of type-I collagenase. Employing the rat liver fibrosis model produced by porcine serum, we also estimated the effect of oral administration of a stable RA analog on the progression of the fibrosis, as well as on hepatic TGF-beta contents. In vitro SC cultures, 9-cis-RA enhanced cellular PA and plasmin levels thereby induced plasmin-mediated activation of latent TGF-beta. Active TGF-beta generated self-stimulated its synthesis as well as that of collagen and suppressed the production of collagenase in an autocrine manner. In in vivo rat models, an RA analog accelerated the porcine serum-induced fibrosis by enhancing TGF-beta contents and, thus, collagen levels in the liver, although the RA analog alone was not fibrogenic. These results suggest that RA exacerbated liver fibrosis, at least in part, by inducing the activation and production of latent TGF-beta in liver SCs.
 ...
PMID:Retinoids exacerbate rat liver fibrosis by inducing the activation of latent TGF-beta in liver stellate cells. 932 35


1 2 3 4 5 6 Next >>