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

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. J. Cell. Biochem. 118: 754-763, 2017. © 2016 Wiley Periodicals, Inc.

Short-Chain Fatty Acids (Except Hexanoic Acid) Lower NF-kB Transactivation, Which Rescues Inflammation-Induced Decreased Apolipoprotein A-I Transcription in HepG2 Cells

“…Indeed, Bai and coworkers have shown that overexpression of C/EBP-β increased the expression of cytokines such as IL-8 [ 28 ]. Furthermore, the ApoA-I promoter has a C/EBP binding site, which indicates that C/EBP-β might be involved in ApoA-I production [ 29 ]. As a result, we suggest in future experiments to investigate the role of SCFAs in rescuing the inflammation-induced reduction in ApoA-I expression by evaluating their effects on the C/EBP- β signaling pathway.…”

Icariin ameliorates endothelial dysfunction in type 1 diabetic rats by suppressing ER stress via the PPARα/Sirt1/AMPKα pathway

“…We next investigated the mechanism of ICA attenuating diabetes-induced endothelial dysfunction through inhibiting ER stress. Activation of PPARα contributes to numerous pathologies by inhibiting ER stress, including diabetes (Chan et al, 2013;Ge et al, 2016), obesity , atherosclerosis (van der Krieken et al, 2017), and cardiovascular diseases (Huang et al, 2017). ICA has been implicated as the activator of PPARα in diabetes (Lu et al, 2014).…”

Apolipoprotein A1 Inhibits the TGF-β1-Induced Endothelial-to-Mesenchymal Transition of Human Coronary Artery Endothelial Cells

“…Apolipoprotein A1 (ApoA-I), the major protein component of HDL, has also been found to have anti-AS activity and to decrease the risk of CVDs [9]. Research has demonstrated the cardiovascular protective effect of ApoA-I by averting cholesterol accumulation in the vascular wall via the promotion of cholesterol efflux from the tissues to the liver for excretion [10].…”