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.
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. J. Cell. Biochem. 118: 754-763, 2017. © 2016 Wiley Periodicals, Inc.
Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P.O. Box 616, Maastricht 6200 MD, The Netherlands.
Sophie E
SE
van der Krieken
Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P.O. Box 616, Maastricht 6200 MD, The Netherlands.
Herman E
HE
Popeijus
Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P.O. Box 616, Maastricht 6200 MD, The Netherlands.
Maurice
M
Konings
Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P.O. Box 616, Maastricht 6200 MD, The Netherlands.
Stefan P J
SP
Dullens
Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P.O. Box 616, Maastricht 6200 MD, The Netherlands.
Ronald P
RP
Mensink
Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P.O. Box 616, Maastricht 6200 MD, The Netherlands.
Jogchum
J
Plat
D016632:Apolipoprotein A-I / Q000096:biosynthesis*; D050197:Atherosclerosis / Q000378:metabolism / Q000517:prevention & control; D002087:Butyrates / Q000494:pharmacology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018938:Caco-2 Cells; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D011345:Fenofibrate / Q000031:analogs & derivatives* / Q000494:pharmacology; D020869:Gene Expression Profiling; D020868:Gene Silencing; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology
D016632:Apolipoprotein A-I; D002087:Butyrates; D022782:CCAAT-Enhancer-Binding Protein-beta; C453899:GW 7647; D047493:PPAR alpha; D010671:Phenylurea Compounds; D012333:RNA, Messenger; D019284:Thapsigargin; C006012:fenofibric acid; D011345:Fenofibrate
APOLIPOPROTEIN A-I (apoA-I); CCAAT/ENHANCER-BINDING PROTEIN (C/EBP)-β; ENDOPLASMIC RETICULUM STRESS (ER-STRESS); INFLAMMATION; PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) α