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

A case of apolipoprotein B-related disorder is reported in which liver fibrosis developed without long term administration of medium chain triglycerides, previously incriminated in the pathogenesis of this lesion. The patient was a young woman in whom the diagnosis of familial homozygous hypobetalipoproteinaemia was made at the age of 21. A first liver specimen taken at diagnosis revealed steatosis, hypertrophic Golgi apparatus and proliferating smooth endoplasmic reticulum. The patient was treated with vitamin A and E supplementation only. Two years later, a second liver biopsy, carried out because of increased serum alanine aminotransferase concentrations, showed fibrosis, mild cytolysis and marked mitochondrial alterations. Hepatic level of vitamin A was increased. This finding supports the hypothesis that liver disease observed in our patient might be an adverse effect of vitamin supplementation. Our observation underlines the importance of including liver function tests in the follow up of patients with apolipoprotein B-related disorders.
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PMID:Liver fibrosis in a patient with familial homozygous hypobetalipoproteinaemia: possible role of vitamin supplementation. 156 67

The ultrastructure of Ito cells was examined in percutaneous needle liver biopsies of 36 patients. In three cases the liver was normal. Four specimens showed mild or moderate fatty degeneration. In the rest of the liver samples various types of fibrosis were seen: in four cases portal, in ten centrilobular, in eight periportal fibrosis and in five cases cirrhosis. In the normal liver Ito cells occurred not only in the Disse spaces but also in the walls of the terminal hepatic venules. In livers showing portal fibrosis the ultrastructure of Ito cells was similar to that seen in the normal liver. In the fibrotic areas of liver samples showing centrilobular or periportal fibrosis or cirrhosis Ito cells localized inside the fibrotic tissue and along the border between the connective tissue and hepatocytes. These interstitial Ito cells contained few lipid, abundant rough endoplasmic reticulum with dilated tubules filled by a flocculant material, well developed Golgi complexes and often bundles of 5 nm thick filaments with densities. These cells also known as activated Ito cells were in places surrounded by immature collagen fibrils and basement membrane fragments. There was a close contact between activated Ito cells and lymphocytes. The ultrastructure of Ito cells localizing in non-fibrotic areas did not differ from that seen in normal liver lobules. These observations suggest that Ito cells are related to fibroblasts and myofibroblasts and play an important role in the pathogenesis of liver fibrosis in humans.
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PMID:Ultrastructure of the Ito cells in liver disease associated with fibrosis. 248 63

In an attempt to elucidate the role of fat-storing cells (FSCs) in liver fibrosis, we investigated the collagen synthesis by FSCs freshly isolated from rats treated with CCl4, with vitamin A, and from untreated rats. FSCs from CCl4-treated rats contained a small number of lipid droplets and an abundant rough endoplasmic reticulum (RER), while those from vitamin A-treated rats showed numerous large lipid droplets and scanty RER. The population doubling times of FSCs isolated from normal, CCl4-treated, and vitamin A-treated rats were 38 +/- 4.3, 24 +/- 2.5, and 48 +/- 6.3 hr, respectively. The rate of collagen synthesis by FSCs from CCl4-treated rats was four- to sixfold enhanced, while collagen synthesis by FSCs from vitamin A-treated rats was suppressed. The ratio of collagen type I to type III produced by FSCs from CCl4 rats was enhanced as compared with control rats (94.7:5.3 vs 87.6:12.4). Therefore, FSCs can be considered to play an important role in the pathogenesis of liver fibrosis.
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PMID:Modulation of collagen synthesis by fat-storing cells, isolated from CCl4- or vitamin A-treated rats. 366 83

Hepatic fibrosis has been induced in rats by low doses of dimethylnitrosamine (DMN) and special attention has been paid to early morphological events. DMN (10 microliter/kg body wt., i.p.) was given 3 days a week for 3 weeks to Sprague-Dawley rats. Liver samples were taken on days 7, 14, 21, 28 and 35 and examined by light and electron microscopy. Hemorrhagic necrosis, mainly centrolobular, was evident on day 7, with disruption of the sinusoidal lining, and widening or disappearance of the spaces of Disse invaded by erythrocytes and lymphocytes. Large granular lymphocytes similar to pit cells were also present in close contact with hepatocytes. At day 14, fibrotic septa were associated with cells bearing 'transitional' features between those of lipocytes, myofibroblasts and fibroblasts. Hepatocytes showed foci of increased smooth endoplasmic reticulum, and altered sinusoidal and canalicular membranes. At day 21, all animals showed nodularity of the parenchyma, with evidence of micronodular cirrhosis associated with ascites in two animals. At day 35 (19 days after cessation of treatment) there was little residual inflammation, but well-defined micronodules were still present in all animals. This shows that, in the rat, 3-week treatment with a low dose of DMN produces micronodular cirrhosis following diffuse hemorrhagic necrosis without steatosis. The response of the animals was uniform and reproducible. Lesions of the sinusoidal wall and of membranes of liver cells associated with the inflammatory reaction appeared prominent.
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PMID:A morphological study of the early stages of hepatic fibrosis induced by low doses of dimethylnitrosamine in the rat. 369 62

In an attempt to elucidate the role of fat-storing cells (FSCs) in alcoholic liver fibrosis, we examined the effects of ethanol and acetaldehyde on collagen synthesis by FSCs isolated from CCl4-treated or normal rats. Isolated FSCs from normal rats showed characteristic lipid droplets in the cytoplasm. FSCs from CCl4-treated rats showed an abundant rough endoplasmic reticulum and a small number of lipid droplets. Collagen synthesis by the cells from CCl4-treated rats was 4-5-fold enhanced as compared with untreated rats. Though ethanol had an inhibitory effect on collagen synthesis by FSCs, acetaldehyde stimulated collagen production by the cells from CCl4-induced hepatic fibrosis, whereas collagen synthesis by the cells from normal rats was not influenced by acetaldehyde. From these results, FSCs are morphologically and functionally changed in liver fibrosis, and the transitional state of FSCs might be important in the pathogenesis of alcoholic liver fibrosis.
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PMID:Effect of acetaldehyde on collagen synthesis by fat-storing cells isolated from rats treated with carbon tetrachloride. 377 50

Hepatic perisinusoidal cells (PSCs) proliferate and are thought to be the principal source of extracellular matrix proteins during the development of liver fibrosis. We have studied the classical model of carbon tetrachloride induced liver fibrosis in order to evaluate the possible modulation of PSCs into a synthetically active and contractile cell: the myofibroblast (MF). At the ultrastructural level, this modulation was characterized by reduction of lipid vacuoles and appearance of a developed rough endoplasmic reticulum as well as of microfilament bundles. On investigating the cytoskeletal equipment of PSCs and MFs using light and electron microscopic immunohistochemistry, we found a heterogeneity of phenotypic features. While typical PSCs in normal and fibrotic livers always contained desmin, MFs expressed alpha-smooth muscle (SM) actin in areas of tissue injury and active fibrogenesis. Cells co-expressing alpha-SM actin and desmin were most prominent in the prevenular zone of the lobule (known to be vulnerable to carbon tetrachloride toxicity) and in developing fibrous septa. As demonstrated by immunogold electron microscopy, labelling of microfilament bundles by alpha-SM actin antibody was noted in PSCs containing lipid droplets in early stages of fibrosis; here MFs gradually accumulated and showed alpha-SM actin containing microfilament bundles. In scar tissue, alpha-SM actin expression decreased in both PSCs and myofibroblasts. Our observations support the concept of phenotypic plasticity of PSCs and confirm, at the ultrastructural level, previous suggestions of modulation of these cells into MFs in the course of liver fibrosis.
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PMID:Modulation of perisinusoidal cell cytoskeletal features during experimental hepatic fibrosis. 846 18

Acetaldehyde, the first product of ethanol in hepatocytes, can react with protein to form acetaldehyde-protein adducts (APAs). Because it has been suggested that these adducts could be involved in the pathogenesis of ethanol-induced hepatic lesions and in fibrogenesis, we performed an ultrastructural immunohistochemical study to precisely define the cellular and subcellular localization of APAs. A preembedding technique of indirect immunoperoxidase was performed in liver biopsy specimens from eight patients with alcoholic liver disease, using a specific antiserum against APAs. In all specimens, APAs were detected in the rough endoplasmic reticulum, in some peroxisomes, and in the cytosol of hepatocytes. In four patients with steatofibrosis or cirrhosis, labeling of Ito cells was also observed. In these cases, the same staining pattern was observed in the cytoplasmic processes of myofibroblasts in areas of fibrogenesis. When isolated rat Ito cells were incubated in the presence of acetaldehyde, APAs were also detected in the cytoplasm. These results show that APA formation occurs in hepatocytes at the sites of acetaldehyde production. Detection of APAs in human and rat Ito cells strongly suggests that acetaldehyde can diffuse into Ito cells and bind to cytoplasmic proteins to form local APAs. Because Ito cells are the main effector cells of liver fibrosis, detection of APAs in these cells points to their possible involvement in liver fibrogenesis.
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PMID:Cellular and subcellular localization of acetaldehyde-protein adducts in liver biopsies from alcoholic patients. 877 71

During a study on the development of atheromatous lesions in rabbits fed a diet with a low or high cholesterol supplement, we found a moderate to pronounced centrolobular liver fibrosis. This fibrosis developed in three stages. Early after supplementation of cholesterol, we observed increased immunoreactivity of collagen types I, III, and IV, and fibronectin, around central veins and in adjacent sinusoids. In the second stage, we observed further increase of collagen and fibronectin immunoreactivity, together with the appearance of alpha-smooth muscle actin (alpha-SM actin)-positive cells and anti-rabbit macrophage monoclonal antibody (RAM 11)-positive cells. In the third stage, we observed large numbers of alpha-SM actin-positive cells, together with heavy deposition of connective tissue proteins in pericentral sinusoids, in addition to focal atrophy of parenchymal cells. By transmission electron microscopy (TEM), fat-storing cells in the pericentral regions were shown to be enlarged, to lose their lipid-droplets, and to acquire dilated rough endoplasmic reticulum corresponding to an activated phenotype. Parenchymal cells were either normal or contained numerous small lipid-droplets. They sometimes were smaller and distorted. Northern hybridization performed on total RNA of whole liver showed an increased level of collagen alpha1(I), alpha1(III), and alpha1(IV) messenger RNA (mRNA) after 24 weeks of low dietary cholesterol supplementation. These data show enhanced expression of extracellular matrix proteins. We conclude that cholesterol overload induces pericentral liver fibrosis in rabbits. The diet clearly activates fat-storing cells to become fibrogenic effector cells. At present, we have no explanation why hypercholesterolemia induces phenotypic transition of fat-storing cells.
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PMID:Centrolobular liver fibrosis in the hypercholesterolemic rabbit. 885 2

We have previously reported increased expression of matrix metalloproteinase-2 (MMP-2) using a rat model of liver fibrosis. However we did not clarify how the precursor of MMP-2 (proMMP-2) was activated. Therefore, we used human liver specimens with chronic hepatitis (CH) and liver cirrhosis (LC) to examine expression of membrane-type-1-MMP (MT1-MMP), which has recently been determined to activate proMMP-2. Northern hybridization studies showed a 5.4- and 1.4-fold increase in MMP-2 expression in CH and LC, respectively, as compared with normal liver. MT1-MMP gene expression simultaneously increased 4.0- and 1.4-fold in CH and LC, respectively. In situ hybridization using 35S-cRNA probes of MMP-2 and MT1-MMP showed prominent silver granules in elongated cells found in the lobules, periportal areas, and fibrous septa of CH and LC samples. These elongated cells expressed alpha-smooth muscle actin by immunohistochemistry. Immunoelectron microscopic examination localized MMP-2 and MT1-MMP to the rough endoplasmic reticulum of stellate cells located in the lobules and periportal areas, or to fibroblasts in the fibrous septa, suggesting that MMP-2 and MT1-MMP were produced by these cells. In addition, cytoplasmic and membranous immunodeposits of both MMPs were found in endothelial cells, Kupffer cells, capillary endothelial cells, and lymphocytes, indicating that activation of proMMP-2 occurs locally. Increased expression of MMP-2 and MT1-MMP was detected in CH and LC, while dual over-expression was found in stellate cells and fibroblasts, possibly resulting in the increase of active MMP-2 in and around these cells. These findings suggest that activated MMP-2 may remodel liver parenchyma during the process of liver fibrosis.
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PMID:Dual expression of matrix metalloproteinase-2 and membrane-type 1-matrix metalloproteinase in fibrotic human livers. 939 93

Heat shock protein (HSP) 47 is a collagen-binding stress protein localized in the endoplasmic reticulum (ER). In addition to stress-inducibility through heat shock element-heat shock factor interaction, the expression of HSP47 under normal conditions always correlates with that of collagens in various cell types and tissues. Both HSP47 and types I and III collagens are also dramatically induced under pathophysiological conditions such as liver fibrosis. HSP47 transiently associates with procollagen in the ER and dissociates from it in the cis-Golgi compartment. Possible functions of HSP47 as a molecular chaperone specific for procollagen are discussed: prevention of nascent procollagen chains from forming aggregates, effect on the modification of procollagen, inhibition of intracellular degradation of procollagen, quality control mechanisms under stress conditions, and effect on the secretion from the ER to the Golgi compartment.
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PMID:Expression and function of heat shock protein 47: a collagen-specific molecular chaperone in the endoplasmic reticulum. 952 58


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