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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

Effect of pioglitazone treatment on hepatic steatosis in DIO mice: (A) body weight; (B) liver weight; (C) liver triglyceride; (D) liver-free fatty acids; and (E) liver histology, hematoxylin and eosin staining, bar = 100 µm. Data are mean ± S.E.M. (n = 8), *p < 0.05, **p < 0.01 vs. Con.
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ijms-16-12213-f002: Effect of pioglitazone treatment on hepatic steatosis in DIO mice: (A) body weight; (B) liver weight; (C) liver triglyceride; (D) liver-free fatty acids; and (E) liver histology, hematoxylin and eosin staining, bar = 100 µm. Data are mean ± S.E.M. (n = 8), *p < 0.05, **p < 0.01 vs. Con.

Mentions: Body weight and liver weight in DIO mice were significantly increased compared to normal chow fed mice (Figure 2A,B). Biochemical analysis of hepatic lipid contents and histopathology also revealed that these obese mice developed manifest hepatic steatosis (Figure 2C–E). Following the 38-day treatment with pioglitazone, liver steatosis was markedly aggravated. The final body weight and liver weight in pioglitazone-treated DIO mice were increased by 15.8% (p < 0.05) and 42.8% (p < 0.05), respectively. Furthermore, the treatment increased liver triglyceride (TG) content from 29.2 ± 4.0 to 81.8 ± 13.3 mg/g liver (p < 0.01) and liver free fatty acids (FFA) content from 1.88 ± 0.1 to 3.16 ± 0.3 μEq/g tissue. This unexpected effect was confirmed by H&E staining of tissue samples (Figure 2E), showing increased lipid stores in pioglitazone treated mice.


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)

Effect of pioglitazone treatment on hepatic steatosis in DIO mice: (A) body weight; (B) liver weight; (C) liver triglyceride; (D) liver-free fatty acids; and (E) liver histology, hematoxylin and eosin staining, bar = 100 µm. Data are mean ± S.E.M. (n = 8), *p < 0.05, **p < 0.01 vs. Con.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-12213-f002: Effect of pioglitazone treatment on hepatic steatosis in DIO mice: (A) body weight; (B) liver weight; (C) liver triglyceride; (D) liver-free fatty acids; and (E) liver histology, hematoxylin and eosin staining, bar = 100 µm. Data are mean ± S.E.M. (n = 8), *p < 0.05, **p < 0.01 vs. Con.
Mentions: Body weight and liver weight in DIO mice were significantly increased compared to normal chow fed mice (Figure 2A,B). Biochemical analysis of hepatic lipid contents and histopathology also revealed that these obese mice developed manifest hepatic steatosis (Figure 2C–E). Following the 38-day treatment with pioglitazone, liver steatosis was markedly aggravated. The final body weight and liver weight in pioglitazone-treated DIO mice were increased by 15.8% (p < 0.05) and 42.8% (p < 0.05), respectively. Furthermore, the treatment increased liver triglyceride (TG) content from 29.2 ± 4.0 to 81.8 ± 13.3 mg/g liver (p < 0.01) and liver free fatty acids (FFA) content from 1.88 ± 0.1 to 3.16 ± 0.3 μEq/g tissue. This unexpected effect was confirmed by H&E staining of tissue samples (Figure 2E), showing increased lipid stores in pioglitazone treated mice.

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