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Effect of Chronic Pioglitazone Treatment on Hepatic Gene Expression Profile in Obese C57BL/6J Mice.

Jia C, Huan Y, Liu S, Hou S, Sun S, Li C, Liu Q, Jiang Q, Wang Y, Shen Z - Int J Mol Sci (2015)

Bottom Line: However, there is a discrepancy between preclinical and clinical data in the literature and the benefits of pioglitazone treatment as well as the precise mechanism of action remain unclear.Pioglitazone treatment resulted in exacerbated hepatic steatosis and increased hepatic triglyceride and free fatty acids concentrations, though significantly increased the glucose infusion rate in hyperinsulinemic-euglycemic clamp test.Gene Ontology based enrichment analysis suggests that inflammation response is transcriptionally downregulated, while lipid metabolism is transcriptionally upregulated.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. jiachunming@imm.ac.cn.

ABSTRACT
Pioglitazone, a selective ligand of peroxisome proliferator-activated receptor gamma (PPARγ), is an insulin sensitizer drug that is being used in a number of insulin-resistant conditions, including non-alcoholic fatty liver disease (NAFLD). However, there is a discrepancy between preclinical and clinical data in the literature and the benefits of pioglitazone treatment as well as the precise mechanism of action remain unclear. In the present study, we determined the effect of chronic pioglitazone treatment on hepatic gene expression profile in diet-induced obesity (DIO) C57BL/6J mice in order to understand the mechanisms of NAFLD induced by PPARγ agonists. DIO mice were treated with pioglitazone (25 mg/kg/day) for 38 days, the gene expression profile in liver was evaluated using Affymetrix Mouse GeneChip 1.0 ST array. Pioglitazone treatment resulted in exacerbated hepatic steatosis and increased hepatic triglyceride and free fatty acids concentrations, though significantly increased the glucose infusion rate in hyperinsulinemic-euglycemic clamp test. The differentially expressed genes in liver of pioglitazone treated vs. untreated mice include 260 upregulated and 86 downregulated genes. Gene Ontology based enrichment analysis suggests that inflammation response is transcriptionally downregulated, while lipid metabolism is transcriptionally upregulated. This may underlie the observed aggravating liver steatosis and ameliorated systemic insulin resistance in DIO mice.

No MeSH data available.


Related in: MedlinePlus

Gene network produced using GeneMania. (A) Gene network of inflammatory response, the network consists of 27 genes (circles) connected by 207 interactions (edges); (B) gene network of lipid metabolic process, the network consists of 55 genes (circles) connected by 442 interactions (edges). The interactions found between these genes are: co-expression (purple lines), co-localization (blue lines), shared protein domains (gray-yellow lines) and predicted (yellow lines). Genes that are within a black filled circle indicate differentially expressed genes, while those within a gray filled circle indicate their interactions.
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ijms-16-12213-f004: Gene network produced using GeneMania. (A) Gene network of inflammatory response, the network consists of 27 genes (circles) connected by 207 interactions (edges); (B) gene network of lipid metabolic process, the network consists of 55 genes (circles) connected by 442 interactions (edges). The interactions found between these genes are: co-expression (purple lines), co-localization (blue lines), shared protein domains (gray-yellow lines) and predicted (yellow lines). Genes that are within a black filled circle indicate differentially expressed genes, while those within a gray filled circle indicate their interactions.

Mentions: To easily identify which genes were closely associated with metabolic disorders such as dysfunction of lipid metabolism and steatosis, gene network analysis was performed using GeneMania (Figure 4). As expected from a trait with highly polygenic architecture of lipid metabolic process and inflammatory response, there were a large number of genes involved in the network, with several connections. The number of interactions for Scd1, Elovl3, Fasn, Elovl5 and Fabp4 in the network was 41, 41, 35, 26, and 20 connections, respectively, and their potential role in determining the effect of pioglitazone is discussed below.


Effect of Chronic Pioglitazone Treatment on Hepatic Gene Expression Profile in Obese C57BL/6J Mice.

Jia C, Huan Y, Liu S, Hou S, Sun S, Li C, Liu Q, Jiang Q, Wang Y, Shen Z - Int J Mol Sci (2015)

Gene network produced using GeneMania. (A) Gene network of inflammatory response, the network consists of 27 genes (circles) connected by 207 interactions (edges); (B) gene network of lipid metabolic process, the network consists of 55 genes (circles) connected by 442 interactions (edges). The interactions found between these genes are: co-expression (purple lines), co-localization (blue lines), shared protein domains (gray-yellow lines) and predicted (yellow lines). Genes that are within a black filled circle indicate differentially expressed genes, while those within a gray filled circle indicate their interactions.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490440&req=5

ijms-16-12213-f004: Gene network produced using GeneMania. (A) Gene network of inflammatory response, the network consists of 27 genes (circles) connected by 207 interactions (edges); (B) gene network of lipid metabolic process, the network consists of 55 genes (circles) connected by 442 interactions (edges). The interactions found between these genes are: co-expression (purple lines), co-localization (blue lines), shared protein domains (gray-yellow lines) and predicted (yellow lines). Genes that are within a black filled circle indicate differentially expressed genes, while those within a gray filled circle indicate their interactions.
Mentions: To easily identify which genes were closely associated with metabolic disorders such as dysfunction of lipid metabolism and steatosis, gene network analysis was performed using GeneMania (Figure 4). As expected from a trait with highly polygenic architecture of lipid metabolic process and inflammatory response, there were a large number of genes involved in the network, with several connections. The number of interactions for Scd1, Elovl3, Fasn, Elovl5 and Fabp4 in the network was 41, 41, 35, 26, and 20 connections, respectively, and their potential role in determining the effect of pioglitazone is discussed below.

Bottom Line: However, there is a discrepancy between preclinical and clinical data in the literature and the benefits of pioglitazone treatment as well as the precise mechanism of action remain unclear.Pioglitazone treatment resulted in exacerbated hepatic steatosis and increased hepatic triglyceride and free fatty acids concentrations, though significantly increased the glucose infusion rate in hyperinsulinemic-euglycemic clamp test.Gene Ontology based enrichment analysis suggests that inflammation response is transcriptionally downregulated, while lipid metabolism is transcriptionally upregulated.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. jiachunming@imm.ac.cn.

ABSTRACT
Pioglitazone, a selective ligand of peroxisome proliferator-activated receptor gamma (PPARγ), is an insulin sensitizer drug that is being used in a number of insulin-resistant conditions, including non-alcoholic fatty liver disease (NAFLD). However, there is a discrepancy between preclinical and clinical data in the literature and the benefits of pioglitazone treatment as well as the precise mechanism of action remain unclear. In the present study, we determined the effect of chronic pioglitazone treatment on hepatic gene expression profile in diet-induced obesity (DIO) C57BL/6J mice in order to understand the mechanisms of NAFLD induced by PPARγ agonists. DIO mice were treated with pioglitazone (25 mg/kg/day) for 38 days, the gene expression profile in liver was evaluated using Affymetrix Mouse GeneChip 1.0 ST array. Pioglitazone treatment resulted in exacerbated hepatic steatosis and increased hepatic triglyceride and free fatty acids concentrations, though significantly increased the glucose infusion rate in hyperinsulinemic-euglycemic clamp test. The differentially expressed genes in liver of pioglitazone treated vs. untreated mice include 260 upregulated and 86 downregulated genes. Gene Ontology based enrichment analysis suggests that inflammation response is transcriptionally downregulated, while lipid metabolism is transcriptionally upregulated. This may underlie the observed aggravating liver steatosis and ameliorated systemic insulin resistance in DIO mice.

No MeSH data available.


Related in: MedlinePlus