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)

It was found that chronic intoxication of rats with acetaldehyde results in a distinct, progressive increase of 5(3)H-proline incorporation into collagen synthesized by liver. At the same time, biosynthesis of other proline-containing (noncollagenous) proteins does not change significantly. The effects are similar to those induced by chronic intoxication of rats with ethanol. Since acetaldehyde is an intermediary metabolite formed during ethanol oxidation in liver, it may be concluded that acetaldehyde is a factor responsible for alcohol-induced liver fibrosis.
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PMID:Chronic intoxication with acetaldehyde stimulates collagen biosynthesis in rat liver. 174 69

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

Cells with electron-microscopic characteristics of myofibroblasts were isolated from baboon liver biopsy specimens by collagenase digestion and Percoll density gradient centrifugation and then cultured. The cultures consisted of only one cell type. By immunofluorescence, these cells synthesized collagen types I, III, and IV and laminin. Typical features of myofibroblasts were maintained throughout many passages in the culture. To study the effects of ethanol (and its oxidation product acetaldehyde and associated metabolite lactate) on myofibroblast collagen synthesis, the cell cultures were incubated for 24 h in a medium containing either 50 mM ethanol, 200 microM acetaldehyde, or 5 mM lactate. The cells did not contain significant alcohol dehydrogenase activity. Acetaldehyde stimulated significantly (p less than 0.05) myofibroblast collagen synthesis without changing noncollagen protein synthesis or proline pools. Lactate caused a significant (p less than 0.02) increase in intracellular proline pool and collagen synthesis. Ethanol itself did not have any effect on collagen synthesis of myofibroblasts. The stimulation of collagen synthesis of hepatic myofibroblasts by acetaldehyde and lactate may contribute to the development of alcoholic liver fibrosis, as alcohol intake is known to elevate acetaldehyde and lactate in tissues and blood.
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PMID:Acetaldehyde and lactate stimulate collagen synthesis of cultured baboon liver myofibroblasts. 638 Dec 14

Liver fibrosis is accompanied by significant increase of collagen content in this organ. Chronic intoxication with ethanol is probably the most popular cause of liver fibrosis. Some experimental and clinical data suggest that acetaldehyde (an intermediary product of ethanol oxidation) is responsible for stimulation of collagen biosynthesis in the liver. It increases collagen gene transcription in fibroblasts. About 90% of exogenous ethanol is oxidized in liver providing an enhanced amount of acetaldehyde which triggers the fibrotic response.
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PMID:Collagen in liver fibrosis induced by ethanol. 749 75

Acetaldehyde, the first product of ethanol oxidation, has been shown to stimulate collagen gene expression and to form protein-acetaldehyde adducts. Because little is known about these adducts in human liver tissue, we assessed, with an immunohistochemical procedure, the presence and location of acetaldehyde-protein adducts in liver biopsy specimens of alcoholic patients. In addition, we correlated the presence of adducts with the progression or subsequent occurrence of liver fibrosis. The group included 106 patients with high alcohol consumption (> 90 gm ethanol/day for the last 5 yr), 10 nonalcoholic patients with normal livers and 23 patients with other liver diseases. Sixty-four of the 106 alcoholic patients had a second liver biopsy, whose specimen was used to assess the progression of liver fibrosis. Polyclonal antibodies were produced against homologous low-density lipoprotein purified from rabbit serum and modified in vitro in the presence of acetaldehyde. Protein-acetaldehyde adducts could be detected by immunohistochemistry in biopsy specimens of 90 alcoholic patients (85%), in none of the 10 nonalcoholic patients with normal livers and in 65% of the patients with nonalcoholic liver disease. Acetaldehyde-modified epitopes were detected in the intracellular and extracellular compartment. Intracellular protein-acetaldehyde adducts were localized in the cytoplasm of hepatocytes with a more intense staining in zone 3. No correlation existed between the intensity of intracellular staining and the histologically assessed severity of liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acetaldehyde-modified epitopes in liver biopsy specimens of alcoholic and nonalcoholic patients: localization and association with progression of liver fibrosis. 750 63

Altered degradation of extracellular matrix has been implicated in the pathogenesis of hepatic fibrosis. We studied the effect of acetaldehyde (AcCHO) on gene expression of matrix-metalloproteinase (MMP)-1 (fibroblast type- interstitial collagenase) and MMP-2 (72 kDa gelatinase-type IV collagenase) in comparison with the AcCHO effect on collagen type I and IV synthesis in cultures of fat-storing cells (FSC) isolated from normal human livers. Cultured human FSC expressed single mRNA transcripts (2.7 and 3.2 kb) specific for MMP-1 and MMP-2, respectively. AcCHO inhibited MMP-1 mRNA levels, whereas it stimulated collagen type I mRNA and protein expression. Opposite AcCHO effects were evident on MMP-2 mRNA and collagen IV synthesis, being MMP-2 up-regulated and collagen IV down-regulated. These data suggest that regulation of MMP-1 and MMP-2 genes by AcCHO may contribute to disruption of the normal basement membrane and its replacement with fibrillar collagens in the early stages of alcoholic liver fibrosis.
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PMID:Acetaldehyde regulates the gene expression of matrix-metalloproteinase-1 and -2 in human fat-storing cells. 793 38

Hepatic fibrosis is an important morphological feature of alcohol-induced liver injury. We previously reported that acetaldehyde stimulates collagen I and fibronectin gene transcription in rat fat-storing cell (FSC) culture. We here evaluated whether acetaldehyde increases Col I and FN gene transcription through the induction of c-fos and c-jun proto-oncogenes and studied the possible role played by protein kinase C (PKC) and c-AMP. FSCs, isolated from rat liver on a Nycodenz density gradient, were exposed to acetaldehyde for 1/2, 1, 3, 6, 12, 24 hr and for 10, 20, 30, 45, 60, 90 min in the experiments for jun and fos expression, respectively. Acetaldehyde produced a rapid and transient induction of fos mRNA (undetectable at t = 0, peak at t = 45 and still evident at t = 90). Jun mRNA was weakly expressed in unstimulated FSCs; acetaldehyde induced a prolonged activation of jun expression up to 24 hr with a peak at 3 hr. To study the role of PKC were repeated the experiments in the presence of Staurosporine and H-7. These inhibitors of PKC activity blocked the stimulatory effect of acetaldehyde on fos and jun mRNA expression. Furthermore, they abolished the stimulatory effect of acetaldehyde on collagen I and fibronectin gene expression by FSCs. Acetaldehyde increased the cell membrane PKC activity in FSC cultures in a dose-dependent way. Intracellular cAMP levels were not significantly modified by acetaldehyde in the first 30 min of incubation. We conclude that acetaldehyde increases procollagen I and fibronectin gene transcription in FSCs, possibly through c-fos and c-jun expression, and that PKC may play a regulatory role in this chain of events.
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PMID:Acetaldehyde induces c-fos and c-jun proto-oncogenes in fat-storing cell cultures through protein kinase C activation. 794 71

Undulin and fibronectin (FN) are large extracellular matrix (ECM) glycoproteins possibly involved in cell-matrix interactions. In this study we analyzed the effect of acetaldehyde and transforming growth factor-beta 1 (TGF-beta 1) on undulin and FN synthesis in cultured fat-storing cells (FSC) isolated from wedge sections of normal human livers. Cultured human FSC expressed two mRNA transcripts (6.5 and 8.5 kb) specific for undulin. Acetaldehyde inhibited both undulin mRNA and protein expression, whereas it had an opposite (stimulatory) effect on FN synthesis. TGF-beta 1 induced a dose-dependent increase of both undulin and FN synthesis in FSC cultures. Furthermore, TGF-beta 1 antagonized the inhibitory effect of acetaldehyde on undulin production and potentiated the stimulatory effect of acetaldehyde on FN synthesis. Since undulin is involved in the supramolecular organization of fibrillar collagens and in their enzymatic degradation, its acetaldehyde-induced inhibition may contribute to ECM rearrangement in the early stages of alcoholic liver fibrosis.
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PMID:Regulation of undulin synthesis and gene expression in human fat-storing cells by acetaldehyde and transforming growth factor-beta 1: comparison with fibronectin. 813 74

Hepatic fibrosis is an important morphological feature of alcohol-induced liver injury. We previously reported that acetaldehyde, but not ethanol can stimulate type I collagen and fibronectin synthesis in cultures of rat fat-storing cells (FSC) by increasing transcription of the specific genes. The effect of lactate and pyruvate was studied on collagen I, III, fibronectin accumulation by cultured rat FSCs and it was investigated whether acetaldehyde could increase procollagen I and fibronectin gene transcription through the formation of protein adducts. Lactate and pyruvate (5, 15 and 25 mmol/l) did not significantly affect collagen I, III and fibronectin production by cultured FSCs. Pyridoxal-phosphate and p-hydroxymecuribenzoate (inhibitors of acetaldehyde-protein adduct formation) blocked the stimulatory effect of acetaldehyde on procollagen I and fibronectin gene transcription. These data suggest that ethanol may act as a liver fibrogenic factor through acetaldehyde, its immediate metabolite, whereas lactate does not seem to play a role. Acetaldehyde might stimulate gene transcription of extracellular matrix components by liver FSCs through the formation of adducts with proteins.
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PMID:Acetaldehyde-protein adducts, but not lactate and pyruvate, stimulate gene transcription of collagen and fibronectin in hepatic fat-storing cells. 815 Oct 99

Apolipoprotein A-I (Apo A-I), a protein produced mainly by hepatocytes, is decreased in the sera of alcoholic patients with liver fibrosis and cirrhosis. To explain this decrease, we investigated possible interactions between liver extracellular matrix (ECM) and Apo A-I. Using a solid-phase binding assay, we evaluated the binding of Apo A-I to the different liver matrix components. Apo A-I bound significantly to fibronectin (FN) (optical density [OD] = 1.11 +/- .26, P = .01) and collagen (C) I (OD = 0.91 +/- 0.22, P = .02) in comparison with bovine serum albumin (BSA) (OD = 0.26 +/- 0.16). Binding of Apo A-I to fibronectin was concentration dependent and saturable. Apo A-I bound also to ECM in vivo because Apo A-I was detected by immunofluorescence on fibrous septa in liver biopsy specimens of alcoholic patients. Because a negative correlation between Apo A-I and liver fibrosis is amplified in alcoholic patients, we investigated whether the in vitro formation of Apo A-I/acetaldehyde complex (adducts) increased the binding of Apo A-I to the ECM. We showed that the amount of Apo A-I that bound to FN was significantly higher with acetaldehyde-modified Apo A-I (OD = 2.18 +/- 0.19, P = .01) than with native Apo A-I. This increase was probably related to the formation and binding of Apo A-I dimers, because immunoblot of in vitro acetaldehyde-modified Apo A-I showed the formation of dimeric Apo A-I. In conclusion, FN binds both native and acetaldehyde-modified Apo A-I. Because FN is deposited early and in excess during liver fibrosis, a storage mechanism of Apo A-I on newly deposited fibronectin would explain, in part, the decrease observed in alcoholic patients with liver fibrosis.
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PMID:Binding of apolipoprotein A-I and acetaldehyde-modified apolipoprotein A-I to liver extracellular matrix. 862 Nov 58


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