Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The farnesoid X receptor (FXR; NR1H4) is a nuclear hormone receptor that functions as the bile acid receptor. In addition to the critical role FXR plays in bile acid metabolism and transport, it regulates a variety of genes important in lipoprotein metabolism. We demonstrate that FXR also plays a role in carbohydrate metabolism via regulation of phosphoenolpyruvate carboxykinase (PEPCK) gene expression. Treatment of either H4IIE or MH1C1 rat hepatoma cell lines as well as primary rat or human hepatocytes with FXR agonists led to stimulation of PEPCK mRNA expression to levels comparable to those obtained with glucocorticoid receptor agonists. We examined the physiological significance of FXR agonist-induced enhancement of PEPCK expression in primary rat hepatocytes. In addition to inducing PEPCK expression in primary hepatocytes, FXR agonists stimulated glucose output to levels comparable to those observed with a glucocorticoid receptor agonist. Consistent with these observations, treatment of C57BL6 mice with GW4064 significantly increased hepatic PEPCK expression. Activation of FXR initiated a cascade involving induction of peroxisome proliferator-activated receptor alpha and TRB3 expression that is consistent with stimulation of PEPCK gene expression via interference with a pathway that may involve Akt-dependent phosphorylation of Forkhead/winged helix transcription factor (FOXO1). The FXR-peroxisome proliferator-activated receptor alpha-TRB3 pathway was conserved in rat hepatoma cell lines, mice, as well as primary human hepatocytes. Thus, in addition to its role in the regulation of lipid metabolism, FXR regulates carbohydrate metabolism.
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PMID:Regulation of carbohydrate metabolism by the farnesoid X receptor. 1571 39

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental and food contaminants with known or suspected carcinogenic properties. In this study, we have evaluated whether PAHs activate the early growth response (EGR-1) gene and bind to peroxisome proliferator-activated receptor alpha (PPAR alpha) and delta (PPAR beta/delta) in cell culture systems. Luciferase reporter systems were employed and several PAHs were evaluated for their ability to activate EGR-1 and PPARs. Some PAHs enhanced EGR-1 expression and activated PPAR alpha and PPAR beta. Among them, benz(a)anthracene was found to act as a relatively potent activator of PPAR alpha and PPAR beta/delta, and to significantly enhance EGR-1 transcription. These in vitro assays were confirmed by Western blot analysis, using cell lysates of tissue samples from mouse trapped at a highly contaminated Superfund site in the Chattanooga Creek floodplain in Chattanooga, Tennessee. We have found that a PPAR target gene, glycogen synthase kinase-3beta (GSK-3beta), was down-regulated and EGR-1 was up-regulated in the mouse samples of Chattanooga Creek. In addition, select PAHs repressed GSK-3beta and induced CYP4A in FaO rat hepatoma cells. In conclusion, PAHs activate PPAR alpha and PPAR beta/delta, and up-regulate EGR-1 expression in vitro as well as in vivo. These data may provide a diversity of PAH activity in several biological pathways.
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PMID:Evaluation of polycyclic aromatic hydrocarbons in the activation of early growth response-1 and peroxisome proliferator activated receptors. 1571 83

Most human hepatocyte cell lines lack a substantial set of liver-specific functions, especially major cytochrome P450 (P450)-related enzyme activities, making them unrepresentative of in vivo hepatocytes. We have used the HepaRG cells, derived from a human hepatocellular carcinoma, which exhibit a high differentiation pattern after 2 weeks at confluency to determine whether they could mimic human hepatocytes for drug metabolism and toxicity studies. We show that when passaged at low density, these cells reversed to an undifferentiated morphology, actively divided, and, after having reached confluency, formed typical hepatocyte-like colonies surrounded by biliary epithelial-like cells. By contrast, when seeded at high density, hepatocyte-like clusters retained their typical differentiated morphology. Transcripts of various nuclear receptors (aryl hydrocarbon receptor, pregnane X receptor, constitutive androstane receptor, peroxisome proliferator-activated receptor alpha), P450s (CYP1A2, 2C9, 2D6, 2E1, 3A4), phase 2 enzymes (UGT1A1, GSTA1, GSTA4, GSTM1), and other liver-specific functions were estimated by reverse transcriptase-quantitative polymerase chain reaction and were found to be expressed, for most of them, at comparable levels in both confluent differentiated and high-density differentiated HepaRG cells and in cultured primary human hepatocytes. For several transcripts, the levels were strongly increased in the presence of 2% dimethyl sulfoxide. Measurement of basal activities of several P450s and their response to prototypical inducers as well as analysis of metabolic profiles and cytotoxicity of several compounds confirmed the functional resemblance of HepaRG cells to primary cultured human hepatocytes. In conclusion, HepaRG cells constitute the first human hepatoma cell line expressing high levels of the major P450s involved in xenobiotic metabolism and represent a reliable surrogate to human hepatocytes for drug metabolism and toxicity studies.
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PMID:Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells. 1620 62

In rats, oxidized fats activate the peroxisome proliferator-activated receptor alpha (PPARalpha), leading to reduced triglyceride concentrations in liver, plasma and very low density lipoproteins. Oxidation products of linoleic acid constitute an important portion of oxidized dietary fats. This study was conducted to check whether the primary lipid peroxidation product of linoleic acid, 13-hydroperoxy-9,11-octadecadienoic acid (13-HPODE), might be involved in the PPARalpha-activating effect of oxidized fats. Therefore, we examined the effect of 13-HPODE on the expression of PPARalpha target genes in the rat Fao and the human HepG2 hepatoma cell lines. In Fao cells, 13-HPODE increased the mRNA concentration of the PPARalpha target genes acyl-CoA oxidase (ACO), cytochrome P450 4A1 and carnitine-palmitoyltransferase 1A (CPT1A). Furthermore, the concentration of cellular and secreted triglycerides was reduced in Fao cells treated with 13-HPODE. Because PPARalpha mRNA was not influenced, we conclude that these effects are due to an activation of PPARalpha by 13-HPODE. In contrast, HepG2 cells seemed to be resistant to PPARalpha activation by 13-HPODE because no remarkable induction of the PPARalpha target genes ACO, CPT1A, mitochondrial HMG-CoA synthase and delta9-desaturase was observed. Consequently, cellular and secreted triglyceride levels were not changed after incubation of HepG2 cells with 13-HPODE. In conclusion, this study shows that 13-HPODE activates PPARalpha in rat Fao but not in human HepG2 hepatoma cells.
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PMID:Differential action of 13-HPODE on PPARalpha downstream genes in rat Fao and human HepG2 hepatoma cell lines. 1621 87

Peroxisome proliferators, such as lipid-lowering fibrate drugs, are agonists for the peroxisome proliferator-activated receptor alpha (PPARalpha). Sustained activation of PPARalpha leads to the development of liver tumors in rodents. Paradoxically, humans appear to be resistant to the induction of peroxisome proliferation and development of liver tumors by peroxisome proliferators. To examine the species differences in response to peroxisome proliferators, a PPARalpha humanized mouse (hPPARalpha) was generated, in which the human PPARalpha was expressed in liver under control of the Tet-OFF system. To evaluate the susceptibility of hPPARalpha mice to peroxisome proliferator-induced hepatocarcinogenesis, a long-term feeding study of Wy-14,643 was carried out. hPPARalpha and wild-type (mPPARalpha) mice were fed either a control diet or one containing 0.1% Wy-14,643 for 44 and 38 weeks, respectively. Gene expression analysis for peroxisomal and mitochondrial fatty acid metabolizing enzymes revealed that both hPPARalpha and mPPARalpha were functional. However, the incidence of liver tumors including hepatocellular carcinoma was 71% in Wy-14,643-treated mPPARalpha mice, and 5% in Wy-14,643-treated hPPARalpha mice. Upregulation of cell cycle regulated genes such as cd1 and Cdks were observed in non-tumorous liver tissue of Wy-14,643-treated mPPARalpha mice, whereas p53 gene expression was increased only in the livers of Wy-14,643-treated hPPARalpha mice. These findings suggest that structural differences between human and mouse PPARalpha are responsible for the differential susceptibility to the peroxisome proliferator-induced hepatocarcinogenesis. This mouse model will be useful for human cancer risk assessment of PPARalpha ligands.
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PMID:Differential susceptibility of mice humanized for peroxisome proliferator-activated receptor alpha to Wy-14,643-induced liver tumorigenesis. 1637 6

The adipose differentiation-related protein (ADFP)/adipophilin belongs to a family of PAT (for perilipin, ADFP, and TIP47) proteins that associate on the surface of lipid droplets (LDs). Except for LD association, a clear role for ADFP has not been found. We demonstrate that ADFP is transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPARalpha) in mouse liver and rat and human hepatoma cells through a highly conserved direct repeat-1(DR-1) element. Although the ADFP mRNA is highly increased by a synthetic PPARalpha agonist, the ADFP protein is only substantially increased in cells containing LDs, such as hepatocytes incubated with fatty acids, and in livers of fasted mice. ADFP is induced by fasting even in the absence of a functional PPARalpha, in marked contrast to the PPARalpha target gene acyl-coenzyme A oxidase-1. Activation of LXRs, which stimulates LD formation through the activation of lipogenesis, does not affect ADFP mRNA levels. TIP47, another PAT member known to be expressed in liver, was unaffected by all treatments. This constitutively expressed PAT member seems to be less transcriptionally regulated than ADFP. These observations suggest that ADFP is primarily a fasting-induced protein in liver that coats the newly synthesized triacylglycerol-containing LDs formed during fasting.
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PMID:PPARalpha activators and fasting induce the expression of adipose differentiation-related protein in liver. 1648 5

Non-alcoholic fatty liver disease (NAFLD) is emerging as a common medical problem. Nonalcoholic steatohepatitis (NASH) is the critical turning point at which NAFLD progresses to more advanced stages such as hepatic fibrosis, cirrhosis and even hepatocellular carcinoma. However, the study of the pathogenic or therapeutic factors involved in NASH has been hampered by the absence of a suitable experimental model. The aim of the present work was to establish a high-fat emulsion-induced rat model of NASH. Male Sprague-Dawley rats were fed a high-fat emulsion via gavage for 6 weeks. Animals were examined for weight gain, serum and hepatic biochemistry, insulin sensitivity, hepatic malondialdehyde (MDA), superoxide dismutase (SOD) and tissue morphology, as well as cytochrome P-450 2E1 (CYP2E1) and peroxisome proliferator-activated receptor alpha (PPARalpha) expression in the liver. The results showed that rats treated with high-fat emulsion became obese, demonstrated abnormal aminotransferase activity, hyperlipoidemia, hyperinsulinemia, hyperglycemia and insulin resistance. The model rats exhibited an increased concentration of serum TNF-alpha, total cholesterol (TC), triglyceride (TG), MDA and reduced SOD levels in the liver. Immunoblot analysis showed that the expression of CYP2E1 was increased, whereas PPARalpha was reduced in the NASH model rat liver. Moreover, morphological evaluation revealed that hepatic steatosis, inflammation and mitochondrial lesions were also reproduced in this model. In conclusion, a practical and repeatable new rat model of steatohepatitis was established by feeding with high-fat emulsion via gavage. This model provides a valuable research tool and reproduces many of the clinical indices of human NASH.
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PMID:High-fat emulsion-induced rat model of nonalcoholic steatohepatitis. 1662 32

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear receptor family of transcription factors and is recognized as the molecular target of the hypolipidemic fibrate drugs. Fibrates promote lipid catabolism by inducing genes involved in fatty acid beta-oxidation. In rodents this is accompanied by peroxisome proliferation, and after chronic dosing hepatocarcinoma, whereas epidemiological studies suggest these adverse events are lacking in humans. Rodents such as rats and mice appear particularly sensitive to PPARalpha-induced peroxisome proliferation while humans are resistant. These findings question the utility of rodent models for safety monitoring of experimental PPARalpha agonists and highlight the need for additional preclinical models that display greater physiological relevance for human response. Thus we have focused on elucidating the molecular mechanism of species-dependent peroxisome proliferation by understanding the PPARalpha-dependent regulation of the acyl-CoA oxidase (AOX) promoter, the rate-limiting step of peroxisomal beta-oxidation. We have chosen the cynomolgus monkey as a model that is modestly responsive to peroxisome proliferation and functionally characterized it against the highly responsive rat and non-responsive human species. We report the identification of a putative peroxisome proliferator response element (PPRE) within the 2.3 kb proximal promoter of the cynomolgus monkey AOX gene. Characterization of these promoters using a series of constitutively active, PPARalpha constructs demonstrate that the PPREs within the proximal cynomolgus and human AOX promoters are non-responsive to PPARalpha whereas the rat PPRE is highly responsive. These findings were verified in vivo using a small molecule PPARalpha agonist. Taken together, we demonstrate concordant regulation of the AOX promoter by PPARalpha in cynomolgus monkeys and humans and suggest that this model is superior to rodent models with respect to preclinical evaluation of PPARalpha agonists.
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PMID:Differential regulation of the cynomolgus, human, and rat acyl-CoA oxidase promoters by PPARalpha. 1682 88

Unlike the livers of humans and mice, and most hepatoma cells, which accumulate triglycerides when treated with microsomal triglyceride transfer protein (MTP) inhibitors, L35 rat hepatoma cells do not express MTP and cannot secrete very low density lipoprotein (VLDL), yet they do not accumulate triglyceride. In these studies we show that transcriptional co-repression of the two lipid transfer proteins, liver fatty acid-binding protein (L-FABP) and MTP, which cooperatively shunt fatty acids into de novo synthesized glycerolipids and the transfer of lipids into VLDL, respectively, act together to maintain hepatic lipid homeostasis. FAO rat hepatoma cells express L-FABP and MTP and demonstrate the ability to assemble and secrete VLDL. In contrast, L35 cells, derived as a single cell clone from FAO cells, do not express L-FABP or MTP nor do they assemble and secrete VLDL. We used these hepatoma cells to elucidate how a conserved DR1 promoter element present in the promoters of L-FABP and MTP affects transcription, expression, and VLDL production. In FAO cells, the DR1 elements of both L-FABP and MTP promoters are occupied by peroxisome proliferator-activated receptor alpha-retinoid X receptor alpha (RXRalpha), with which PGC-1beta activates transcription. In contrast, in L35 cells the DR1 elements of both L-FABP and MTP promoters are occupied by chicken ovalbumin upstream promoter transcription factor II, and transcription is diminished. The combined findings indicate that peroxisome proliferator-activated receptor alpha-RXRalpha and PGC-1beta coordinately up-regulate L-FABP and MTP expression, by competing with chicken ovalbumin upstream promoter transcription factor II for the DR1 sites in the proximal promoters of each gene. Additional studies show that ablation of L-FABP prevents hepatic steatosis caused by treating mice with an MTP inhibitor. Our findings show that reducing both L-FABP and MTP is an effective means to reduce VLDL secretion without causing hepatic steatosis.
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PMID:Coordinate transcriptional repression of liver fatty acid-binding protein and microsomal triglyceride transfer protein blocks hepatic very low density lipoprotein secretion without hepatosteatosis. 1695 Jul 64

During the acute phase response, cytokines induce marked alterations in lipid metabolism including an increase in serum triglyceride levels and a decrease in hepatic fatty acid oxidation, in bile acid synthesis, and in high-density lipoprotein levels. Here we demonstrate that tumor necrosis factor (TNF) and interleukin 1 (IL-1), but not IL-6, decrease the expression of retinoid X receptor alpha (RXRalpha), peroxisome proliferator-activated receptor alpha (PPARalpha), PPARgamma, liver X receptor alpha (LXRalpha), and coactivators PPARgamma coactivator 1alpha (PGC-1alpha), PGC-1beta, and steroid receptor coactivator 1 (SRC-1) in Hep3B human hepatoma cells. In addition, treatment of mice with TNF and IL-1 also decreased RXRalpha, PPARalpha, PPARgamma, LXRalpha, and PGC-1alpha messenger RNA (mRNA) levels in the liver. These decreases were accompanied by reduced binding of nuclear extracts to RXR, PPAR, and LXR response elements and decreased luciferase activity driven by PPAR and LXR response elements. In addition, the mRNA levels of proteins regulated by PPARalpha (carnitine palmitoyltransferase 1alpha) and LXR (sterol regulatory element binding protein) were decreased in Hep3B cells treated with TNF or IL-1. Finally, using constructs of the LXRalpha promoter or the PGC-1alpha promoter linked to luciferase, we were able to demonstrate that a decrease in transcription contributes to the reduction in mRNA levels of nuclear hormone receptors and coactivators. Thus, our results suggest that decreased expression of nuclear hormone receptors RXRalpha, PPARalpha, PPARgamma, and LXRalpha, as well as coactivators PGC-1alpha, PGC-1beta, and SRC-1 may contribute to the cytokine-induced alterations in hepatic lipid metabolism during the acute phase response.
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PMID:Tumor necrosis factor and interleukin 1 decrease RXRalpha, PPARalpha, PPARgamma, LXRalpha, and the coactivators SRC-1, PGC-1alpha, and PGC-1beta in liver cells. 1722 43


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