C/EBP‐β Is Differentially Affected by PPARα Agonists Fenofibric Acid and GW7647, But Does Not Change Apolipoprotein A‐I Production During ER‐Stress and Inflammation

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Abstract
Increasing apolipoproteinA-I (apoA-I) production may be anti-atherogenic. Thus, there is a need to identify regulatory factors involved. Transcription of apoA-I involves peroxisome-proliferator-activated-receptor-alpha (PPARα) activation, but endoplasmic reticulum (ER) -stress and inflammation also influence apoA-I production. To unravel why PPARα agonist GW7647 increased apoA-I production compared to PPARα agonist fenofibric acid (FeAc) in human hepatocellular carcinoma (HepG2) and colorectal adenocarcinoma (CaCo-2) cells, gene expression profiles were compared. Microarray analyses suggested CCAAT/enhancer-binding-protein-beta (C/EBP-β) involvement in the FeAc condition. Therefore, C/EBP-β silencing and isoform-specific overexpression experiments were performed under ER-stressed, inflammatory and non-inflammatory conditions. mRNA expression of C/EBP-β, ATF3, NF-IL3 and GDF15 were upregulated by FeAc compared to GW7647 in both cell lines, while DDIT3 and DDIT4 mRNA were only upregulated in HepG2 cells. This ER-stress related signature was associated with decreased apoA-I secretion. After ER-stress induction by thapsigargin or FeAc addition, intracellular apoA-I concentrations decreased, while ER-stress marker expression (CHOP, XBP1s, C/EBP-β) increased. Cytokine addition increased intracellular C/EBP-β levels and lowered apoA-I concentrations. Although a C/EBP binding place is present in the apoA-I promoter, C/EBP-β silencing or isoform-specific overexpression did not affect apoA-I production in inflammatory, non-inflammatory and ER-stressed conditions. Therefore, C/EBP-β is not a target to influence hepatic apoA-I production. This article is protected by copyright. All rights reserved
Funding Information
  • Dutch Technology Foundation STW, which is part of the Netherlands Organisation for Scientific Research (NWO), and which is partly funded by the Ministry of Economic Affairs (11349)

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