title: Link Between ER-Stress, PPAR-Alpha Activation, and BET Inhibition in Relation to Apolipoprotein A-I Transcription in HepG2 Cells.
abstract: Activating transcription factor peroxisome proliferator-activated receptor alpha (PPARα) may increase apoA-I transcription. Furthermore, Bromodomain and Extra-Terminal domain (BET) protein inhibitors increase, whereas Endoplasmic Reticulum (ER) stress decreases apoA-I transcription. We examined possible links between these processes as related to apoA-I transcription in HepG2 cells. JQ1(+), thapsigargin, and GW7647 were used to induce, respectively BET inhibition, ER-stress, and PPARα activation. Expression of ER-stress markers (CHOP, XBP1s) was analyzed by western blotting. PPARα, KEAP1 (marker for BET inhibition), and apoA-I mRNAs were measured using qPCR. ER-stress and BET inhibition both decreased PPARα mRNA expression and activity, but did not interfere with each other, as ER-stress did not change KEAP1 and JQ1(+) did not influence ER-stress marker production. Interestingly, PPARα activation and BET-inhibition diminished ER-stress marker production and rescued apoA-I transcription during existing ER-stress. We conclude that the ER-stress mediated reduction in apoA-I transcription could be partly mediated via the inhibition of PPARα mRNA expression and activity. In addition, BET inhibition increased apoA-I transcription, even if PPARα production and activity were decreased. Finally, both BET inhibition and PPARα activation ameliorate the apoA-I lowering effect of ER-stress and are therefore interesting targets to elevate apoA-I transcription. J. Cell. Biochem. 118:2161-2167, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, MD Maastricht, 616-6200, the Netherlands.
authors.forename: Sophie E
authors.initials: SE
authors.lastname: van der Krieken
authors.affiliation: Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, MD Maastricht, 616-6200, the Netherlands.
authors.forename: Herman E
authors.initials: HE
authors.lastname: Popeijus
authors.affiliation: Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, MD Maastricht, 616-6200, the Netherlands.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Mensink
authors.affiliation: Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, MD Maastricht, 616-6200, the Netherlands.
authors.forename: Jogchum
authors.initials: J
authors.lastname: Plat
mesh_terms: D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D016632:Apolipoprotein A-I; D000072019:Kelch-Like ECH-Associated Protein 1; D047493:PPAR alpha; D011506:Proteins; D012333:RNA, Messenger; C505693:APOA1 protein, human; C431364:KEAP1 protein, human; C000624329:bromodomain and extra-terminal domain protein, human; D000092468:Bromodomain Containing Proteins
keywords: APOLIPOPROTEIN A-I (apoA-I); BROMODOMAIN AND EXTRA-TERMINAL (BET) PROTEIN INHIBITION; ENDOPLASMIC RETICULUM STRESS (ER-STRESS); PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) ALPHA; TRANSCRIPTION