ATF6α Stimulates Cholesterogenic Gene Expression and<i>de Novo</i>Cholesterol Synthesis

Maruyama, Ryuto; Kamoshida, Yuki; Shimizu, Makoto; Inoue, Jun; Sato, Ryuichiro

doi:10.1271/bbb.130295

Cited by 10 publications

(8 citation statements)

References 16 publications

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“…The activated Atf6 transcriptionally controls various genes functioning in protein folding and the maintenance of ER homeostasis [ 12 37 ]. In addition, Atf6 regulates numerous genes in lipid metabolism; specifically, it stimulates cholesterogenic and lipogenic genes by antagonizing sterol regulatory element-binding protein 2 (SREBP2) [ 38 39 ]. Supporting this notion, Atf6 null mice are more insulin-sensitive and contain less serum triglyceride (TG) [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

ER Stress Activates the TOR Pathway through Atf6

Allen¹,

Seo

2018

Journal of Molecular Signaling

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Cellular signaling pathways are often interconnected. They accurately and efficiently regulate essential cell functions such as protein synthesis, cell growth, and survival. The target of rapamycin (TOR) signaling pathway and the endoplasmic reticulum (ER) stress response pathway regulate similar cellular processes. However, the crosstalk between them has not been appreciated until recently and the detailed mechanisms remain unclear. Here, we show that ER stress-inducing drugs activate the TOR signaling pathway in S2R+ Drosophila cells. Activating transcription factor 6 (Atf6), a major stress-responsive ER transmembrane protein, is responsible for ER stress-induced TOR activation. Supporting the finding, we further show that knocking down of both site-1/2 proteases (S1P/S2P), Atf6 processing enzymes, are necessary to connect the two pathways.

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Section: Discussionmentioning

confidence: 99%

ER Stress Activates the TOR Pathway through Atf6

Allen¹,

Seo

2018

Journal of Molecular Signaling

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“…ATF6a is reported to be a key molecule in the control of triglyceride and cholesterol metabolism. 21,24,25 To address the role of ATF6a in lipid metabolism of the kidney, especially PTCs, which predominantly utilize fatty acids as an energy source, we employed the HK-2 cell line overexpressing dominant active ATF6a (aATF6a) or dominant negative ATF6a (dnATF6a) by utilizing a lentiviral expression system ( Figure 1a). aATF6a overexpression upregulated the downstream targets BiP and CHOP (C/EBP homologous protein), whereas dnATF6a or empty vector infection (Mock) did not (Figure 1b), indicating that ectopically expressed aATF6a is functional in HK-2.…”

Section: Atf6a Activation Enhances Lipid Accumulation Via Derangementmentioning

confidence: 99%

ATF6α downregulation of PPARα promotes lipotoxicity-induced tubulointerstitial fibrosis

Jao

Nangaku

et al. 2019

Kidney International

105

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“…In addition, ER stress can promote phosphorylation of the eukaryotic translation initiation factor 2 (eIF2A) through accumulation and aggregation of unfolded proteins [ 14 , 15 ]. Many studies have demonstrated that persistent or severe ER stress can induce unexpected apoptosis [ 16 – 18 ]. More research is needed to understand the mechanisms of ER stress-associated apoptosis in SCI, although ER stress responses seem to divert towards apoptosis pathways in neurons and oligodendrocytes following SCI in the adult rat [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Zbtb38 is a novel target for spinal cord injury

Cai

Zhang

et al. 2017

Oncotarget

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Spinal cord injury (SCI) is currently incurable since treatments applied to clinic are limited to minimizing secondary complications and the mechanisms of injury-induced spinal cord damage are poorly understood. Zbtb38, also called CIBZ, is highly expressed in spinal cord and it functions as a negative regulator in SCI-induced apoptosis. We show here that Zbtb38 is downregulated under endoplasmic reticulum (ER) stress, which promotes ER stress-associated apoptosis in human bone marrow neuroblastoma cells. In the traumatic SCI mice, ER stress presented in injured spinal cord induced repression of Zbtb38 expression and triggered Zbtb38-mediated apoptosis. ChIP-QPCR analysis revealed that ATF4, an ER-stress inducible transcription factor, directly activated Zbtb38 transcription by binding to the Zbtb38 promoter. However, this binding was significantly reduced following SCI, leading to a sharp decrease in Zbtb38 expression. Restoring Zbtb38 function in injured spinal cord by injection of lentivirus containing Zbtb38 into SCI mice, significantly alleviated secondary damage of spinal cord with decreased ER stress-associated apoptosis and partially recovered spinal cord functions. These findings demonstrate that restoration of Zbtb38 expression can reduce secondary tissue damage after SCI, and suggest that a therapeutic strategy for targeting Zbtb38 may promote functional recovery of spinal cord for patients with SCI.

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ATF6α Stimulates Cholesterogenic Gene Expression andde NovoCholesterol Synthesis

Cited by 10 publications

References 16 publications

ER Stress Activates the TOR Pathway through Atf6

ER Stress Activates the TOR Pathway through Atf6

ATF6α downregulation of PPARα promotes lipotoxicity-induced tubulointerstitial fibrosis

Zbtb38 is a novel target for spinal cord injury

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