Regulation of albumin expression in fetal rat hepatocytes cultured under proliferative conditions: Role of epidermal growth factor and hormones

Juan, Carmen; Benito, Manuel; Fabregat, Isabel

doi:10.1002/jcp.1041520113

Cited by 38 publications

(15 citation statements)

References 49 publications

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“…As we had previously described that the response of fetal hepatocytes to extracellular stimuli is clearly dependent on their proliferative state, 34 we decided to incubate the cells with dexamethasone (100 nmol/L) in the absence or in the presence of a mitogenic stimulus, i.e., EGF, at 20 ng/mL, and/or TNF-␣. After 10 minutes of stimulation, hepatocytes were lysed and protein extracts were analyzed for JNK activity (Fig.…”

Section: Effect Of Dexamethasone On Jnk Activity Induced By Tnf-␣mentioning

confidence: 99%

Glucocorticoid Receptor Down–Regulates C–Jun Amino Terminal Kinases Induced by Tumor Necrosis Factor α in Fetal Rat Hepatocyte Primary Cultures

et al. 1999

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The effect of dexamethasone on Jun N-terminal kinase (JNK) activity was assayed by using fetal hepatocytes in primary culture. The addition of tumor necrosis factor ␣ (TNF-␣) caused an increase in JNK in a dose-and timedependent manner. We show that activation of JNK by this extracellular signal is inhibited by dexamethasone in a dose-dependent fashion. This inhibitory effect was observed in cells treated for 10 minutes with dexamethasone in the presence of protein phosphatase inhibitors such as orthovanadate or okadaic acid, or in cells previously treated with actinomycin D. Glucocorticoid receptor (GR) can be precipitated with the fusion protein, GST-c-Jun (1-79), bound to agarose beads. However, the inhibitory effect of glucocorticoids on JNK activity was also observed using ATF-2 as substrate. In addition, dexamethasone inhibits JNK phosphorylation induced by TNF-␣. Finally, we show that GR can also be phosphorylated in tyrosine residues in response to TNF-␣ and epidermal growth factor (EGF) upon ligand-binding. Our results suggest that the antiinflammatory effect of glucocorticoids on the inflammatory pathways induced by TNF-␣ can be explained, at least in part, by modulating JNK activity through a direct proteinprotein interaction; the JNK phosphorylation and tyrosinephosphorylation state of GR may be regulatory steps also involved in that effect. (HEPATOLOGY 1999;29:849-857.)

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Section: Effect Of Dexamethasone On Jnk Activity Induced By Tnf-␣mentioning

confidence: 99%

Glucocorticoid Receptor Down–Regulates C–Jun Amino Terminal Kinases Induced by Tumor Necrosis Factor α in Fetal Rat Hepatocyte Primary Cultures

et al. 1999

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“…These cells are able to carry out both proliferation and differentiation processes simultaneously. We have shown that some growth factors such as epidermal growth factor (EGF), hepatocyte growth factor, or transforming growth factor-␣ (20,21) are able to induce DNA replication in these cells, whereas some hormones (glucagon, noradrenaline, glucocorticoids), by themselves or in synergism with the positive growth factors, regulate the expression of some liver-specific genes (22)(23)(24). TGF-␤ inhibits the EGF and/or hepatocyte growth factor-induced DNA synthesis and modulates protooncogene and liver-specific gene expression in these cells (20,21,25,26).…”

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confidence: 99%

Apoptosis Induced by Transforming Growth Factor-β in Fetal Hepatocyte Primary Cultures

Sánchez

Álvarez

Benito

et al. 1996

Journal of Biological Chemistry

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Transforming growth factor-␤ (TGF-␤), a growth regulator of fetal hepatocytes in primary culture, also regulates death of these cells. Dose-response analysis showed that the TGF-␤ concentration needed to induce hepatocyte death (2.5 ng/ml) was 5 times that needed to inhibit growth in these cells (0.5 ng/ml). In response to TGF-␤, hepatocytes induced DNA fragmentation and the appearance of nuclei with a DNA content lower than 2C (diploid content), typical of a programmed cell death model. TGF-␤-induced apoptosis in fetal hepatocytes was preceded by an induction of reactive oxygen species production and a decrease in the glutathione intracellular content, indicating that this factor induces oxidative stress in fetal hepatocytes. Studies performed to analyze levels of c-fos mRNA, a gene whose expression is modulated by redox state, demonstrated that only high, apoptotic concentrations of TGF-␤ (2.5 ng/ml) produced an increase in the mRNA levels of this gene, the level of induction being similar to that found when cells were incubated in the presence of tert-butyl hydroperoxide. Gel mobility shift assays showed that the c-fos-induced expression was coincident with an increase in AP-1 activity. Finally, cell death induced by TGF-␤ in fetal hepatocytes was partially blocked by radical scavengers, which decreased the percentage of apoptotic cells, whereas these agents did not modify the growth-inhibitory effect elicited by TGF-␤ in these cells. In summary, the results presented in this paper provide evidence for the involvement of an oxidative process in the apoptosis elicited by TGF-␤ in fetal hepatocytes.

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“…Analysis of the albuhepatocytes in primary culture respond to epidermal growth factor and hormones (noradrenaline, glucocorti-min and b-actin mRNA levels in livers from rats cotreated with TAM and SAM showed that neither the coids), increasing albumin mRNA level. 12 Growth factors and hormones secreted in response to the TAM-increases in albumin and b-actin mRNA levels at 1 to 2 days nor the decrease in albumin expression at 4 induced hepatotoxicity in the rat 30 could account for the enhanced albumin mRNA levels found under our days (Fig. 2) were observed.…”

Section: Discussionmentioning

confidence: 69%

Changes in rat liver gene expression induced by thioacetamide: Protective role ofS-adenosyl-L-methionine by a glutathione-dependent mechanism

Mesa¹,

Carrizosa²,

Martínez-Honduvilla³

et al. 1996

Hepatology

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Chronic liver damage induced by thioacetamideChronic liver dysfunction caused by cirrhosis is a (TAM) was accompanied by changes in the expression relatively common disease and is accompanied by alterof genes related to growth (b-actin) and function (albu-ations that affect the normal function of the liver. 1 Numin and haptoglobin) of the liver. Their messenger RNA merous animal models of cirrhosis have been developed (mRNA) levels increased during the first days after TAM that more or less resemble the human disease. The administration, but 4 to 7 days after prolonged treat-slowly developing thioacetamide (TAM)-induced rat ment with this drug, liver gene expression was consider-cirrhosis has proven to be morphologically well defined able decreased. TAM-induced changes in albumin and and uniform 2 and seems to resemble major features of b-actin mRNA levels were prevented by cotreatment the human disease. 3 S-adenosyl-L-methionine (SAM), with S-adenosyl-L-methionine (SAM). We have investi-the principal methyl-group donor and metabolite of megated the possible involvement of glutathione in the protective mechanism of SAM. Firstly, we found that TAM thionine, has increasingly been used in the therapy of treatment in the rat induced changes in liver glutathi-chronic liver disease. 4,5 SAM treatment prevents carone disulfide (GSSG) levels, with a concomitant increase bon tetrachloride 6 and acetaminophen 7 hepatotoxicity in the glutathione reductase enzymatic activity, these and produces significant reduction of hepatic necrosis changes being abolished when animals were cotreated induced by TAM. 8 The mechanism by which SAM inwith TAM and SAM. Secondly, when rats were pre-hibits liver disorders is poorly understood. It could be treated with buthionine sulfoximine (BSO), a glutathi-related to an increase in glutathione level induced by one synthesis inhibitor, before thioacetamide adminis-SAM in chronic liver disease 9 or to its ability to induce tration, the beneficial effect of SAM on liver gene protein methylation. 10 expression was completely abolished. These results wereThe objective of our investigation has been to study confirmed by assaying the alanine transaminase serum activity, a parameter of liver injury. TAM-treated ani-the changes in liver gene expression after short-term mals had increases in this serum enzyme, this effect be-TAM administration in the rat, and the possible protecing partially blocked by SAM. However, in BSO-pre-tive effect of SAM on these alterations. We have setreated rats, the protective effect of SAM was impaired. lected two genes, albumin and b-actin, as markers of Taking together all these results, we propose a glutathi-liver function and growth, respectively. Production of one-dependent mechanism in the SAM protection plasma proteins is one of the main liver functions. Seagainst TAM hepatotoxicity in the rat. (HEPATOLOGY rum albumin is the most abundant protein synthesized recently shown that under proliferative conditions (i.e.,

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Regulation of albumin expression in fetal rat hepatocytes cultured under proliferative conditions: Role of epidermal growth factor and hormones

Cited by 38 publications

References 49 publications

Glucocorticoid Receptor Down–Regulates C–Jun Amino Terminal Kinases Induced by Tumor Necrosis Factor α in Fetal Rat Hepatocyte Primary Cultures

Glucocorticoid Receptor Down–Regulates C–Jun Amino Terminal Kinases Induced by Tumor Necrosis Factor α in Fetal Rat Hepatocyte Primary Cultures

Apoptosis Induced by Transforming Growth Factor-β in Fetal Hepatocyte Primary Cultures

Changes in rat liver gene expression induced by thioacetamide: Protective role ofS-adenosyl-L-methionine by a glutathione-dependent mechanism

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