Link Between ER-Stress, PPAR-Alpha Activation, and BET Inhibition in Relation to Apolipoprotein A-I Transcription in HepG2 Cells

Activating transcription factor peroxisome proliferator-activated receptor alpha (PPAR) 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 PPAR activation. Expression of ER-stress markers (CHOP, XBP1s) was analyzed by western blotting. PPAR, KEAP1 (marker for BET inhibition), and apoA-I mRNAs were measured using qPCR. ER-stress and BET inhibition both decreased PPAR 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, PPAR 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 PPAR mRNA expression and activity. In addition, BET inhibition increased apoA-I transcription, even if PPAR production and activity were decreased. Finally, both BET inhibition and PPAR 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. (c) 2016 Wiley Periodicals, Inc.