Activating Transcription Factor 4F

It is likely that atf4 regulates lipid metabolism by regulating pgc1, a suppressor expression. ¹⁸Another possibility is that the ER stress response is involved in ATF4 regulation. ¹⁸ATF4 is a key factor in this process and has been recently shown to induce intracellular lipid accumulation through the activation of SREBPs . ¹⁸An ATF4 deficiency can cause the ER stress response to failing, which contributes to the decreased expression of SREBP1c in WAT and BAT in experimental mice. ¹⁸

The atf4 is induced by stress as a downstream effector of the Perk branch of the unfolded protein response. ¹¹In ER stress activation, PERK is activated by autophosphorylation, which in turn phosphorylates eIF2a, resulting in the inhibition of global protein translation. ¹¹Malabanan et al.42 have presented a comprehensive series of experiments linking ATF4 to intimal thickening after injury, and identified both upstream and downstream associated growth factor pathways, providing additional insights into orchestrated signaling pathways and the activation of transcription factors in vascular disease. ¹¹

Reversible phosphorylation of serine 51 of a subunit of eukaryotic translation initiation factor 2 (eif2a) is a highly conserved regulatory event that is activated in response to various strains. ⁹In mammals, it is known that four protein kinases couple different upstream stress signals to eIF2a phosphorylation. ⁹However, it also favors enhanced translation of a selected number of mRNAs containing short open reading frames upstream. ⁹One of the proteins for which translation is enhanced activates transcription factor 4 (ATF4), a member of the ATF subfamily of the leucine zipper transcription factor superfamily (bZIP). ⁹

As is responsible for increasing the sensitivity of transcription induction of these autophagy genes as a function of leucine concentration. ⁹In fact, transcription of p62, Nbr1 and Atg7 was up-regulated by a leucine concentration of 100 μM, while transcription of the other autophagy genes remained uninduced. ⁹ It was suggested that the interaction of ATF4 with CHOP might increase its binding affinity to AARE. ⁹In the case of ATG7, in addition to its crucial role in the autophagic process, this protein could also be involved in other mechanisms, including cell cycle regulation, and thus must be available with a protein content maintained under starvation conditions. ⁹
A major task of atf4 is to mediate the induction of a gene expression program called integrated stress response (isr) involved in amino acid metabolism, differentiation, metastasis, angiogenesis, resistance to oxidative stress, and drug resistance.⁹ Autophagy is a highly conserved cellular process of lysosomal degradation of proteins and organelles. ⁹It is involved in the renewal of cell organelles and the maintenance of energy levels, protein synthesis and essential metabolic processes through the recycling of amino acids and nutrients. ⁹Recently, it has been reported that ER stress and severe hypoxia induce the transcription of the essential autophagy gene Map1lc3b by the activity of ATF4. ⁹In the context of amino acid deficiency, it has been reported that GCN2 kinase activation and eIF2a phosphorylation are required to induce autophagy in yeast and mammals. ⁹

Studying the mechanisms by which chop can affect the balance between autophagy and apoptosis in response to cellular stress provides additional insights into these important processes. ⁹Under conditions of stress and hunger, autophagy plays a key role in the degradation of cell organelles and cytoplasmic content, allowing cells to recycle amino acids and nutrients to maintain protein synthesis and ATP production. ⁹Various signal transduction pathways are known to regulate the induction of autophagy, such as mTORC1 and AMPK, in response to nutrient availability. ⁹
The transcription factors that are regulated by BDNF and that mediate the genomic responses to BDNF and that underlie many of its effects have been less extensively characterized. ⁶In light of these problems, researchers, therefore, explored the possibility that BDNF regulates neuronal ATF4 expression. ⁶Here, researchers report that BDNF promotes a rapid and sustained increase in ATF4 mRNA and protein levels in cortical and hippocampal neurons through activation of TrkB receptors. ⁶The increase of the ATF4 protein occurs in processes as well as in cell bodies and nuclei. ⁶
The direct effect of atf4 on the lipogenic pathway and liver insulin transduction in liver cells needs to be further investigated. ¹⁴To better understand the relationship between ATF4 and liver lipogenesis, the present study investigated the direct effect of ERS on liver lipogenesis in HepG2 cells. ¹⁴Subsequently, the influence of ATF4 deficiency or overexpression on the hepatic lipogenic pathway and insulin signal transduction in HepG2 cells was observed. ¹⁴

The development of new therapeutic interventions requires a comprehensive understanding of the mechanisms by which excess liver lipid develops and leads to hepatic insulin resistance. ¹⁴Hepatic steatosis is the fundamental pathophysiological change that exists during the development of NAFLD, and it has been shown that increased de novo lipogenesis is a mechanism by which fatty liver develops. ¹⁴Recent studies using genetic or dietary models of fatty liver have shown that there is an important link between hepatic steatosis and ER stress, as well as the physiological role of the unfolded protein response (UPR) sensors in lipid homeostasis . ¹⁴However, the direct effect of ERS inhibition and induction on lipogenesis has not been studied in hepatocytes in vitro. ¹⁴

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Cited Sources

• https://en.wikipedia.org/wiki/ATF4 ⁰
• https://www.sciencedirect.com/topics/neuroscience/activating-transcription-factor-4 ¹
• https://www.nature.com/articles/s41598-017-01041-7 ²
• https://omim.org/entry/604064?search=chromosome_group%3AA&highlight=A ³
• http://www.jbc.org/content/286/37/32416.full ⁴
• https://www.prospecbio.com/activating_transcription_factor ⁵
• https://www.frontiersin.org/articles/10.3389/fnmol.2018.00062/full ⁶
• https://www.hindawi.com/journals/bmri/2015/974615/ ⁷
• https://insight.jci.org/articles/view/88646 ⁸
• https://academic.oup.com/nar/article/41/16/7683/2411270 ⁹
• https://iovs.arvojournals.org/article.aspx?articleid=2126353 ¹⁰
• https://www.ahajournals.org/doi/full/10.1161/circresaha.117.311066 ¹¹
• https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0007583 ¹²
• https://www.mendeley.com/catalogue/activating-transcription-factor-4-promotes-esophageal-squamous-cell-carcinoma-invasion-metastasis-mi/ ¹³
• https://www.spandidos-publications.com/mmr/14/2/1649 ¹⁴
• https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/induction-of-autophagy-through-the-activating-transcription-factor-4-atf4dependent-amino-acid-response-pathway-in-maternal-skeletal-muscle-may-function-as-the-molecular-memory-in-response-to-gestational-protein-restriction-to-alert-offspring-to-maternal-nutrition/A16E203400BA6F50DDB7E7A24C9A3F9D ¹⁵
• https://www.tandfonline.com/doi/full/10.1080/15384101.2015.1120929 ¹⁶
• https://ashpublications.org/blood/article/99/3/736/53500/Targeted-disruption-of-the-activating ¹⁷
• https://iubmb.onlinelibrary.wiley.com/doi/full/10.1002/iub.605 ¹⁸
• https://www.cell.com/trends/endocrinology-metabolism/pdf/S1043-2760(17)30100-5.pdf ¹⁹

 
Key Words:  leucine concentration    protein synthesis     direct effect    amino acids     fatty liver     stress     hepg2 cells     hepatic steatosis     additional insights     transcriptional factors