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Gene Expression Changes Induced by PPAR Gamma Agonists in Animal and Human Liver.

Rogue A, Spire C, Brun M, Claude N, Guillouzo A - PPAR Res (2010)

Bottom Line: Although PPARγ is expressed at a much lower level in liver than in adipose tissue, PPARγ agonists exert various PPARγ-dependent effects in liver in addition to PPARγ-independent effects.Differences in effects are dependent on the choice of agonist and experimental conditions in rodent animal studies and in rodent and human liver cell cultures.These effects are much more pronounced in obese and diabetic liver.

View Article: PubMed Central - PubMed

Affiliation: UMR INSERM U991, Faculté des Sciences Pharmaceutiques et Biologiques, 35043 Rennes, France.

ABSTRACT
Thiazolidinediones are a class of Peroxisome Proliferator Activated Receptor γ (PPARγ) agonists that reduce insulin resistance in type 2 diabetic patients. Although no detectable hepatic toxicity has been evidenced in animal studies during preclinical trials, these molecules have nevertheless induced hepatic adverse effects in some treated patients. The mechanism(s) of hepatotoxicity remains equivocal. Several studies have been conducted using PCR analysis and microarray technology to identify possible target genes and here we review the data obtained from various in vivo and in vitro experimental models. Although PPARγ is expressed at a much lower level in liver than in adipose tissue, PPARγ agonists exert various PPARγ-dependent effects in liver in addition to PPARγ-independent effects. Differences in effects are dependent on the choice of agonist and experimental conditions in rodent animal studies and in rodent and human liver cell cultures. These effects are much more pronounced in obese and diabetic liver. Moreover, our own recent studies have shown major interindividual variability in the response of primary human hepatocyte populations to troglitazone treatment, supporting the occurrence of hepatotoxicity in only some individuals.

No MeSH data available.


Related in: MedlinePlus

Two-dimensional hierarchical clustering of gene expression profiles induced by TRO treatment in primary human hepatocytes from five donors and HepaRG cells. The clustering was generated by using the Resolver system software with an agglomerative algorithm, the Ward's min variance link heuristic criteria, and the Euclidean distance metric. Cultures and microarray analysis as in Table 2.
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fig1: Two-dimensional hierarchical clustering of gene expression profiles induced by TRO treatment in primary human hepatocytes from five donors and HepaRG cells. The clustering was generated by using the Resolver system software with an agglomerative algorithm, the Ward's min variance link heuristic criteria, and the Euclidean distance metric. Cultures and microarray analysis as in Table 2.

Mentions: Up to now, studies on human hepatocytes have been limited to a few donors (one to three), and no interdonor variability has been considered. Since interdonor variability in response to chemical inducers or inhibitors is well established, we recently compared the effects of TRO in human hepatocyte cultures from five donors after a 24-hour treatment using pangenomic microarrays (Rogue et al., unpublished data). Two-dimensional hierarchical clustering of gene expression profiles showed that hepatocyte populations separated according to the donor and not to the TRO concentration (Figure 1). It exhibited two separate clusters: one with donors 4 and 5 and the second with donors 1, 2, and 3. The number of genes modulated by TRO greatly varied as a function of the donor and drug concentration. At 5 and 20 μM, TRO modulated 5754 and 7266 genes, respectively, in at least one donor but only 4 and 29 genes in the 5 donors, respectively (Figure 2). The small subset of common deregulated genes in hepatocyte cultures from several donors is in agreement with the findings reported by Goyak et al. [88], showing that the number of modulated genes deregulated in ten populations of human hepatocytes by arochlor 1254, di(2-ethylhexyl)phthalate, and phenobarbital did not exceed 0.1%. In our study, among the few genes deregulated in the five donors by 5 μM TRO, only two genes involved in oxidative stress, namely, mannose binding lectin 2 (MBL2) and serum/glucocorticoid regulated kinase 2 (SGK2), were induced. Genes involved in lipid metabolism, such as FABP1 were deregulated only by 20 μM TRO in all the donors. Several PPAR target genes, such as CYP4A1, CPT1, or CD36, were induced in the two hepatocyte cultures treated by 40 μM TRO.


Gene Expression Changes Induced by PPAR Gamma Agonists in Animal and Human Liver.

Rogue A, Spire C, Brun M, Claude N, Guillouzo A - PPAR Res (2010)

Two-dimensional hierarchical clustering of gene expression profiles induced by TRO treatment in primary human hepatocytes from five donors and HepaRG cells. The clustering was generated by using the Resolver system software with an agglomerative algorithm, the Ward's min variance link heuristic criteria, and the Euclidean distance metric. Cultures and microarray analysis as in Table 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2963138&req=5

fig1: Two-dimensional hierarchical clustering of gene expression profiles induced by TRO treatment in primary human hepatocytes from five donors and HepaRG cells. The clustering was generated by using the Resolver system software with an agglomerative algorithm, the Ward's min variance link heuristic criteria, and the Euclidean distance metric. Cultures and microarray analysis as in Table 2.
Mentions: Up to now, studies on human hepatocytes have been limited to a few donors (one to three), and no interdonor variability has been considered. Since interdonor variability in response to chemical inducers or inhibitors is well established, we recently compared the effects of TRO in human hepatocyte cultures from five donors after a 24-hour treatment using pangenomic microarrays (Rogue et al., unpublished data). Two-dimensional hierarchical clustering of gene expression profiles showed that hepatocyte populations separated according to the donor and not to the TRO concentration (Figure 1). It exhibited two separate clusters: one with donors 4 and 5 and the second with donors 1, 2, and 3. The number of genes modulated by TRO greatly varied as a function of the donor and drug concentration. At 5 and 20 μM, TRO modulated 5754 and 7266 genes, respectively, in at least one donor but only 4 and 29 genes in the 5 donors, respectively (Figure 2). The small subset of common deregulated genes in hepatocyte cultures from several donors is in agreement with the findings reported by Goyak et al. [88], showing that the number of modulated genes deregulated in ten populations of human hepatocytes by arochlor 1254, di(2-ethylhexyl)phthalate, and phenobarbital did not exceed 0.1%. In our study, among the few genes deregulated in the five donors by 5 μM TRO, only two genes involved in oxidative stress, namely, mannose binding lectin 2 (MBL2) and serum/glucocorticoid regulated kinase 2 (SGK2), were induced. Genes involved in lipid metabolism, such as FABP1 were deregulated only by 20 μM TRO in all the donors. Several PPAR target genes, such as CYP4A1, CPT1, or CD36, were induced in the two hepatocyte cultures treated by 40 μM TRO.

Bottom Line: Although PPARγ is expressed at a much lower level in liver than in adipose tissue, PPARγ agonists exert various PPARγ-dependent effects in liver in addition to PPARγ-independent effects.Differences in effects are dependent on the choice of agonist and experimental conditions in rodent animal studies and in rodent and human liver cell cultures.These effects are much more pronounced in obese and diabetic liver.

View Article: PubMed Central - PubMed

Affiliation: UMR INSERM U991, Faculté des Sciences Pharmaceutiques et Biologiques, 35043 Rennes, France.

ABSTRACT
Thiazolidinediones are a class of Peroxisome Proliferator Activated Receptor γ (PPARγ) agonists that reduce insulin resistance in type 2 diabetic patients. Although no detectable hepatic toxicity has been evidenced in animal studies during preclinical trials, these molecules have nevertheless induced hepatic adverse effects in some treated patients. The mechanism(s) of hepatotoxicity remains equivocal. Several studies have been conducted using PCR analysis and microarray technology to identify possible target genes and here we review the data obtained from various in vivo and in vitro experimental models. Although PPARγ is expressed at a much lower level in liver than in adipose tissue, PPARγ agonists exert various PPARγ-dependent effects in liver in addition to PPARγ-independent effects. Differences in effects are dependent on the choice of agonist and experimental conditions in rodent animal studies and in rodent and human liver cell cultures. These effects are much more pronounced in obese and diabetic liver. Moreover, our own recent studies have shown major interindividual variability in the response of primary human hepatocyte populations to troglitazone treatment, supporting the occurrence of hepatotoxicity in only some individuals.

No MeSH data available.


Related in: MedlinePlus