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.

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

“…ApoA-I mRNA expression in HepG2 cells was lower under inflammatory conditions as compared to normal conditions ( Figure 1 ). In agreement with our previous studies [ 15 ], the positive control JQ1(+) and the negative control thapsigargin (Thap) respectively increased and decreased ApoA-I mRNA expression (both p < 0.001). Also, under inflammatory conditions, JQ1(+) significantly ( p < 0.001) increased ApoA-I gene expression, whereas Thap even further decreased ApoA-1 gene expression ( p < 0.001) compared with the normal condition ( Figure 1 ).…”

“…All together, these results of C4 suggested that PPARα transactivation might be involved in the effects of SCFAs on ApoA-I expression in normal and inflammatory conditions. This is also in agreement with our previous study in which we found a clear role for PPARα transactivation on ApoA-I mRNA transcription in non-inflamed HepG2 cells [ 15 ]. Moreover, it seems that BET inhibition does not contribute to the effects of SCFAs on ApoA-I during inflammatory conditions, since KEAP1 was not reduced in inflamed HepG2 cells.…”

In vitro effects of sitosterol and sitostanol on mitochondrial respiration in human brown adipocytes, myotubes and hepatocytes

“…HepG2 cells were grown in MEM supplemented with 10% FCS, sodium pyruvate and non-essential amino acids and pen/strep as described [18]. Collection and differentiation of human primary myotubes have been described previously [19].…”

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Role of autophagy in a model of obesity: A long‑term high fat diet induces cardiac dysfunction

“…3 ). As the reduction of PPARα expression may inhibit ERS ( 12 ), the level of ERS was tested. During ER stress, the level of CHOP expression is elevated and its role in programmed cell death of ER-stressed cells is correlated with its role in promoting protein synthesis and oxidative stress inside the ER ( 13 ).…”