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Peroxisome proliferator-activated receptor-alpha gene level differently affects lipid metabolism and inflammation in apolipoprotein E2 knock-in mice.

ABSTRACT: OBJECTIVE: Peroxisome proliferator-activated receptor-? (PPAR?) is a ligand-activated transcription factor that controls lipid metabolism and inflammation. PPAR? is activated by fibrates, hypolipidemic drugs used in the treatment of dyslipidemia. Previous studies assessing the influence of PPAR? agonists on atherosclerosis in mice yielded conflicting results, and the implication of PPAR? therein has not been assessed. The human apolipoprotein E2 knock-in (apoE2-KI) mouse is a model of mixed dyslipidemia, atherosclerosis, and nonalcoholic steatohepatitis (NASH). The aim of this study was to analyze, using homo- and heterozygous PPAR?-deficient mice, the consequences of quantitative variations of PPAR? gene levels and their response to the synthetic PPAR? agonist fenofibrate on NASH and atherosclerosis in apoE2-KI mice. METHODS AND RESULTS: Wild-type (+/+), heterozygous (+/-), and homozygous (-/-) PPAR?-deficient mice in the apoE2-KI background were generated and subjected to a Western diet supplemented with fenofibrate or not supplemented. Western diet-fed PPAR?-/- apoE2-KI mice displayed an aggravation of liver steatosis and inflammation compared with PPAR?+/+ and PPAR?+/- apoE2-KI mice, indicating a role of PPAR? in liver protection. Moreover, PPAR? expression was required for the fenofibrate-induced protection against NASH. Interestingly, fenofibrate treatment induced a similar response on hepatic lipid metabolism in PPAR?+/+ and PPAR?+/- apoE2-KI mice, whereas, for a maximal antiinflammatory response, both alleles of the PPAR? gene were required. Surprisingly, atherosclerosis development was not significantly different among PPAR?+/+, PPAR?+/-, and PPAR?-/- apoE2-KI mice. However, PPAR? gene level determined both the antiatherosclerotic and vascular antiinflammatory responses to fenofibrate in a dose-dependent manner. CONCLUSIONS: These results demonstrate a necessary but quantitatively different role of PPAR? in the modulation of liver metabolism, inflammation, and atherogenesis.

SUBMITTER: Lalloyer F

PROVIDER: S-EPMC3327645 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Peroxisome proliferator-activated receptor-alpha gene level differently affects lipid metabolism and inflammation in apolipoprotein E2 knock-in mice.

Lalloyer Fanny F Wouters Kristiaan K Baron Morgane M Caron Sandrine S Vallez Emmanuelle E Vanhoutte Jonathan J Baugé Eric E Shiri-Sverdlov Ronit R Hofker Marten M Staels Bart B Tailleux Anne A

Arteriosclerosis, thrombosis, and vascular biology 20110407 7

<h4>Objective</h4>Peroxisome proliferator-activated receptor-α (PPARα) is a ligand-activated transcription factor that controls lipid metabolism and inflammation. PPARα is activated by fibrates, hypolipidemic drugs used in the treatment of dyslipidemia. Previous studies assessing the influence of PPARα agonists on atherosclerosis in mice yielded conflicting results, and the implication of PPARα therein has not been assessed. The human apolipoprotein E2 knock-in (apoE2-KI) mouse is a model of mix ...[more]

PMID: 21474829

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Project description:Ampullary cancer is a rare periampullary cancer currently with no targeted therapeutic agent. It is important to develop a deeper understanding of the carcinogenesis of ampullary cancer. We attempted to explore the characteristics of ampullary cancer in our dataset and a public database, followed by a search for potential drugs. We used a bioinformatics pipeline to analyze complementary (c)DNA microarray data of ampullary cancer and surrounding normal duodenal tissues from five patients. A public database from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) was applied for external validation. Bioinformatics tools used included the Gene Set Enrichment Analysis (GSEA), Database for Annotation, Visualization and Integrated Discovery (DAVID), MetaCore, Kyoto Encyclopedia of Genes and Genomes (KEGG), Hallmark, BioCarta, Reactome, and Connectivity Map (CMap). In total, 9097 genes were upregulated in the five ampullary cancer samples compared to normal duodenal tissues. From the MetaCore analysis, genes of peroxisome proliferator-activated receptor alpha (PPARA) and retinoid X receptor (RXR)-regulated lipid metabolism were overexpressed in ampullary cancer tissues. Further a GSEA of the KEGG, Hallmark, Reactome, and Gene Ontology databases revealed that PPARA and lipid metabolism-related genes were enriched in our specimens of ampullary cancer and in the NCBI GSE39409 database. Expressions of PPARA messenger (m)RNA and the PPAR-α protein were higher in clinical samples and cell lines of ampullary cancer. US Food and Drug Administration (FDA)-approved drugs, including alvespimycin, trichostatin A (a histone deacetylase inhibitor), and cytochalasin B, may have novel therapeutic effects in ampullary cancer patients as predicted by the CMap analysis. Trichostatin A was the most potent agent for ampullary cancer with a half maximal inhibitory concentration of < 0.3 μM. According to our results, upregulation of PPARA and lipid metabolism-related genes are potential pathways in the carcinogenesis and development of ampullary cancer. Results from the CMap analysis suggested potential drugs for patients with ampullary cancer.

Dataset Information

Peroxisome proliferator-activated receptor-alpha gene level differently affects lipid metabolism and inflammation in apolipoprotein E2 knock-in mice.

Publications

Peroxisome proliferator-activated receptor-alpha gene level differently affects lipid metabolism and inflammation in apolipoprotein E2 knock-in mice.

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