Contrasting hepatocytic peroxisome proliferation, lipofuscin accumulation and cell turnover for the hepatocarcinogens Wy-14,643 and clofibric acid

Marsman, Daniel S.; Goldsworthy, Thomas L.; Popp, James A.

doi:10.1093/carcin/13.6.1011

Cited by 71 publications

(47 citation statements)

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“…*, signi®cantly different from control, P < 0.05. the livers of rats treated for 13 wk with the PPs WY, GEM, and DBP. This subchronic time-point was chosen based on previous work demonstrating that feeding WY for this period results in a 16-fold increase in hepatocellular replication over that in nontreated rats [36]. Figure 5A shows that the mRNA levels of all three genes were markedly decreased after WY treatment, and quanti®cation ( Figure 5B) revealed that they were expressed at levels approximating 30% of those of untreated controls.…”

Section: Effect Of Subchronic Pp Treatments On App Gene Mrna Abundancementioning

confidence: 99%

Hepatic expression of acute-phase protein genes during carcinogenesis induced by peroxisome proliferators

1999

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Concern exists regarding peroxisome proliferator (PP) xenobiotic exposure because many PPs are potent hepatocarcinogens in rodents. The mechanism of carcinogenicity induced by PPs is atypical compared with those of other hepatocarcinogens in that the former appears to involve alterations in expression of PP-activated receptor (PPAR) target genes rather than direct mutagenicity. To begin to identify some of these genes, we used differential display to compare mRNA expression between hepatic adenomas and adjacent non-tumor liver from rats fed the potent PP Wy-14643 (WY) for 78 wk. Here, we report increased expression of the acute-phase protein (APP) gene alpha-1 antitrypsin (AT) and decreased expression of alpha2-urinary globulin in the tumors. Similar changes were seen in hepatic adenomas induced by a diethylnitrosamine and phenobarbital protocol, indicating a lack of specificity for PP-induced tumors. Additional APP genes, including ceruloplasmin, haptoglobin, beta-fibrinogen, and alpha1-acid glycoprotein were also upregulated in WY-induced tumors but were downregulated in the livers of rats administered a different PP for 13 wk. Mice treated with either WY or di(2-ethylhexyl) phthalate for 3 wk had decreased hepatic AT expression but increased expression of ceruloplasmin and haptoglobin. PPARalpha-null mice showed no hepatic APP gene alteration after PP treatment but had higher basal expression than did wild-type controls. We conclude that PPARalpha activation by several different PPs leads to dysregulation of hepatic APP gene expression in rats and mice. This dysregulation may indicate alterations in cytokine signaling networks regulating both APP gene expression and hepatocellular proliferation.

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Section: Effect Of Subchronic Pp Treatments On App Gene Mrna Abundancementioning

confidence: 99%

Hepatic expression of acute-phase protein genes during carcinogenesis induced by peroxisome proliferators

1999

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“…Although PPs are carcinogenic in rats and mice, there are marked species differences in responses, and these compounds have not been found to induce peroxisome proliferation and hepatocarcinogenesis in humans (29). The mechanism of the hepatocarcinogenic effect of PPAR␣ activators in rats and mice is not well understood; however, it is thought to involve increased proliferation and oxidative stress induced by these compounds (4,47). For example, PPAR␣ agonists such as ciprofibrate have been implicated in modulating the Article published online before print.…”

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confidence: 99%

Liver gene expression in rats in response to the peroxisome proliferator-activated receptor-α agonist ciprofibrate

Yadetie

Lægreid

Bakke

et al. 2003

Physiological Genomics

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Fibrate class hypolipidemic drugs such as ciprofibrate activate the peroxisome proliferator-activated receptor-α (PPARα), which is involved in processes including lipid metabolism and hepatocyte proliferation in rodents. We examined the effects of ciprofibrate (50 mg/kg body wt per day for 60 days) on liver gene expression in rats using cDNA microarrays. The 60-day dosing period was chosen to elucidate both the metabolic and proliferative actions of this substance, while avoiding confounding effects from the hepatic carcinogenesis seen during more long-term stimulation. Ciprofibrate changed the expression of many genes including previously known PPARα agonist-responsive genes involved in processes such as lipid metabolism and inflammatory responses. In addition, many novel candidate genes involved in sugar metabolism, transcription, signal transduction, cell proliferation, and stress responses appeared to be differentially regulated in ciprofibrate-dosed rats. Ciprofibrate also resulted in significant increases in liver weight and hepatocyte proliferation. The cDNA microarray results were confirmed by Northern blot analysis for selected genes. This study thus identifies many genes that appear to be differentially regulated in ciprofibrate-dosed rats, and some of these are potential targets of PPARα. The functional diversity of these candidate genes suggests that most of them are likely to be differentially regulated as indirect consequence of the many processes affected by ciprofibrate in rodent liver. Although caution is advisable in the interpretation of genome-wide expression data, the genes identified in the present study provide candidates for further studies that may give new insight into the mechanisms of action of peroxisome proliferators.

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“…Although lipofuscin occurs frequently in benign cells, it has been linked indirectly to carcinogenesis by its association with cell senescence and increased peroxisomal oxidation. [22][23][24] Both of these cell conditions, wherein lipofuscin is a morphological correlate, can result in carcinogenesis through oxidative damage to the DNA. For instance, carcinogenesis often arises in senescent cells that are still competent for replication.…”

Section: Discussionmentioning

confidence: 99%

Pigmented hepatocellular adenomas have a high risk of atypia and malignancy

et al. 2015

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Pigment deposition is occasionally seen in hepatocellular adenomas. Several reports suggest that pigmented hepatocellular adenomas have increased risk of malignancy, but these tumors remain incompletely understood. To determine the frequency of pigment deposition, we evaluated and classified 109 well-differentiated hepatocellular neoplasms that were originally diagnosed or submitted in consultation as hepatocellular adenomas and found 27 (25%) pigmented tumors. All were negative on iron stain and in three cases electron microscopy confirmed the pigment was lipofuscin. The lipofuscin intensely stained with glypican-3 in most cases (89%). Of the 27 pigmented tumors, 11 cases (41%) were classified as hepatocellular adenomas, 7 cases (27%) were classified as atypical hepatocellular adenomas/hepatocellular neoplasms of uncertain malignant potential, and 9 cases (33%) were reclassified as well-differentiated hepatocellular carcinomas. Four (of 9) hepatocellular carcinomas arose in pigmented hepatocellular adenomas, giving a rate of malignant transformation in pigmented hepatocellular adenomas of 27%. Of the total 27 pigmented tumors, 78% were in women and 22% in men, but interestingly only men had tumors classified as hepatocellular carcinoma or hepatocellular neoplasm of uncertain malignant potential. Also of note, a total of 10 individuals (37%) had multiple hepatocellular neoplasms but in 9 of these cases the other adenomas were non-pigmented. Importantly, in cases with multiple hepatocellular neoplasms, only the pigmented hepatocellular neoplasms had atypia or malignancy. Genotype-phenotype classification of the pigmented tumors showed different subtypes: HNF1α inactivated (48%), β-catenin activated (26%), inflammatory (15%), concurrently β-catenin activated and inflammatory in 1 hepatocellular adenoma, concurrently HNF-1α inactivated and β-catenin activated in 1 hepatocellular adenoma, and unclassified in 1 hepatocellular carcinoma. In conclusion, hepatocellular adenomas with lipofuscin pigment are a heterogeneous group of adenomas, with HNF-1α inactivation being the commonest genotype. They have an increased risk of atypia and malignancy, especially in males.

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Contrasting hepatocytic peroxisome proliferation, lipofuscin accumulation and cell turnover for the hepatocarcinogens Wy-14,643 and clofibric acid

Cited by 71 publications

References 0 publications

Hepatic expression of acute-phase protein genes during carcinogenesis induced by peroxisome proliferators

Hepatic expression of acute-phase protein genes during carcinogenesis induced by peroxisome proliferators

Liver gene expression in rats in response to the peroxisome proliferator-activated receptor-α agonist ciprofibrate

Pigmented hepatocellular adenomas have a high risk of atypia and malignancy

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