scholarly journals TRiC activates the unfolded protein response and protects starved stem cells by modulating energy and lipid metabolism during planarian regeneration

2019 ◽  
Author(s):  
Óscar Gutiérrez-Gutiérrez ◽  
Daniel A. Felix ◽  
Alessandra Salvetti ◽  
Anne Thems ◽  
Stefan Pietsch ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Lipid Metabolism ◽  
Unfolded Protein Response ◽  
Stem Cell Proliferation ◽  
Unfolded Protein ◽  
Cell Genome ◽  
The Unfolded Protein Response ◽  
Protein Response

SummaryFasting protects stem cells and increases stem cell functionality through mechanisms which are not fully understood. Planarians are not only able to regenerate their bodies, but also to stand long periods of starvation by shrinking in size. This adaptation is possible because of a large population of adult stem cells which indefinitely self-renew even under starved conditions and thus confer planarians with immortality. How starved planarians are able to maintain healthy stem cells and to fuel stem cell proliferation allowing regeneration is unknown. Here we found the TCP-1 ring complex (TRiC) to be upregulated in starved stem cells. Down-regulation of TRiC impairs planarian regenerative response by inducing stem cell genome instability, mitotic defects and stem cell death which translates into stem cell exhaustion. This regulation is specific of starvation since feeding planarians prevents the phenotype. Importantly we found that TRiC activates the unfolded protein response (UPR) which allows a convergent regulation of cellular energy and lipid metabolism in starved planarians thus permitting the high energy demanding regenerative mitotic response. We identified a novel mechanism through which starvation protects the somatic stem cell genome allowing for unlimited stem cell proliferation and regeneration.

scholarly journals The Unfolded Protein Response Is Associated with Cancer Proliferation and Worse Survival in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4443
Author(s):  
Ankit Patel ◽  
Masanori Oshi ◽  
Li Yan ◽  
Ryusei Matsuyama ◽  
Itaru Endo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Unfolded Protein Response ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Immune Cell ◽  
Histological Grade ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Hepatocellular carcinoma is a leading cause of cancer death worldwide. The unfolded protein response (UPR) has been revealed to confer tumorigenic capacity in cancer cells. We hypothesized that a quantifiable score representative of the UPR could be used as a biomarker for cancer progression in HCC. In this study, a total of 655 HCC patients from 4 independent HCC cohorts were studied to examine the relationships between enhancement of the UPR and cancer biology and patient survival in HCC utilizing an UPR score. The UPR correlated with carcinogenic sequence and progression of HCC consistently in two cohorts. Enhanced UPR was associated with the clinical parameters of HCC progression, such as cancer stage and multiple parameters of cell proliferation, including histological grade, mKI67 gene expression, and enrichment of cell proliferation-related gene sets. The UPR was significantly associated with increased mutational load, but not with immune cell infiltration or angiogeneis across independent cohorts. The UPR was consistently associated with worse survival across independent cohorts of HCC. In conclusion, the UPR score may be useful as a biomarker to predict prognosis and to better understand HCC.

HIV protease inhibitors activate the unfolded protein response and disrupt lipid metabolism in primary hepatocytes

2006 ◽  
Vol 291 (6) ◽  
pp. G1071-G1080 ◽  
Author(s):  
Huiping Zhou ◽  
Emily C. Gurley ◽  
Sirikalaya Jarujaron ◽  
Hong Ding ◽  
Youwen Fang ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Unfolded Protein Response ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Mrna Levels ◽  
Primary Hepatocytes ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Treatment of human immunodeficiency virus (HIV)-infected patients with HIV protease inhibitors (PIs) has been associated with serious lipid disturbances. However, the incidence and degree of impaired lipid metabolism observed in the clinic vary considerably between individual HIV PIs. Our previous studies demonstrated that HIV PIs differ in their ability to increase the levels of transcriptionally active sterol regulatory element-binding proteins (SREBPs), activate the unfolded protein response (UPR), induce apoptosis, and promote foam cell formation in macrophages. In the present study, we examined the effects of three HIV PIs, including amprenavir, atazanavir, and ritonavir, on the UPR activation and the expression of key genes involved in lipid metabolism in primary rodent hepatocytes. Both atazanavir and ritonavir activated the UPR, induced apoptosis, and increased nuclear SREBP levels, but amprenavir had no significant effect at the same concentrations. In rat primary hepatocytes, cholesterol 7α-hydroxylase (CYP7A1) mRNA levels were significantly decreased by atazanavir (38%) and ritonavir (56%) but increased by amprenavir (90%); 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase mRNA levels were increased by amprenavir (23%) but not by ritonavir and atazanavir; low-density lipoprotein receptor mRNA was increased by atazanavir (20%) but not by amprenavir and ritonavir. Similar results were obtained in mouse primary hepatocytes. Atazanavir and ritonavir also decreased CYP7A1 protein levels and bile acid biosynthesis, while amprenavir had no significant effect. The current results may help provide a better understanding of the cellular mechanisms of HIV PI-induced dyslipidemia and also provide useful information to help predict clinical adverse effects in the development of new HIV PIs.

scholarly journals Hepatocellular autophagy modulates the unfolded protein response and fasting-induced steatosis in mice

2016 ◽  
Vol 311 (4) ◽  
pp. G599-G609 ◽  
Author(s):  
Wilhelmus J. Kwanten ◽  
Yves-Paul Vandewynckel ◽  
Wim Martinet ◽  
Benedicte Y. De Winter ◽  
Peter P. Michielsen ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Unfolded Protein Response ◽  
Liver Parenchyma ◽  
Ductular Reaction ◽  
Nonalcoholic Fatty Liver ◽  
Unfolded Protein ◽  
Hepatocellular Apoptosis ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response ◽  
Protein Response

Autophagy and the unfolded protein response (UPR) are key cellular homeostatic mechanisms and are both involved in liver diseases, including nonalcoholic fatty liver disease (NAFLD). Although increasing but conflicting results link these mechanisms to lipid metabolism, their role and potential cross talk herein have been poorly investigated. Therefore, we assessed the effects of hepatocyte-specific autophagy deficiency on liver parenchyma, the UPR, and lipid metabolism. Adult hepatocellular-specific autophagy-deficient mice ( Atg7F/FAlb-Cre+) were compared with their autophagy-competent littermates ( Atg7+/+Alb-Cre+). Livers were analyzed by electron microscopy, histology, real-time qPCR, and Western blotting. Atg7F/FAlb-Cre+mice developed hepatomegaly with significant parenchymal injury, as shown by inflammatory infiltrates, hepatocellular apoptosis, pericellular fibrosis, and a pronounced ductular reaction. Surprisingly, the UPR exhibited a pathway-selective pattern upon autophagy deficiency. The activity of the adaptive activating transcription factor 6 (ATF6) pathway was abolished, whereas the proapoptotic protein kinase RNA-like ER kinase pathway was increased compared with Atg7+/+Alb-Cre+mice. The inositol-requiring enzyme-1α signal was unaltered. Fasting-induced steatosis was absent in Atg7F/FAlb-Cre+mice. Remarkably, some isolated islands of fat-containing and autophagy-competent cells were observed in these livers. Hepatocellular autophagy is essential for parenchymal integrity in mice. Moreover, in the case of autophagy deficiency, the three different UPR branches are pathway selectively modulated. Attenuation of the ATF6 pathway might explain the observed impairment of fasting-induced steatosis. Finally, autophagy and lipid droplets are directly linked to each other.

Abstract 17305: The ER Unfolded Protein Response Effector, ATF6, Promotes Proliferation and Maintains Pluripotency in Cardiac Stem Cells

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Winston T Stauffer ◽  
Shirin Doroudgar ◽  
Haley N Stephens ◽  
Erik A Blackwood ◽  
Christopher C Glembotski
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Viability ◽  
Unfolded Protein Response ◽  
Cardiac Stem Cells ◽  
Antioxidant Gene ◽  
Unfolded Protein ◽  
Proliferation And Differentiation ◽  
Protein Response

Recent studies have suggested that multipotent stem cells residing in the adult heart, called cardiac stem cells (CSCs), mitigate damage in the infarcted or failing heart. Investigating the factors governing CSC proliferation and differentiation is key to understanding what role these cells play in the heart and in future therapeutic strategies. Additionally, activating transcription factor 6 (ATF6), an effector of the endoplasmic reticulum (ER) unfolded protein response (UPR), plays critical roles in development, as well as in the differentiation of certain stem cell types, though it has not been studied in this regard in the heart. Our lab has demonstrated that ATF6 in cardiac myocytes is cardioprotective in vivo during ischemia/reperfusion partly by virtue of its ability to induce an antioxidant gene program that reduces damaging reactive oxygen species (ROS). However, ATF6, and its involvement in antioxidant gene induction, have not been studied in CSCs. Therefore, here we hypothesized that activation of the ATF6 branch of the UPR in CSCs is important for their proliferation and differentiation, given that ROS is known to be essential for these processes. To address this hypothesis, we subjected cultured mouse CSCs to simulated ischemia and observed increased ATF6 target gene mRNA levels. This demonstrates that, despite their undifferentiated status, CSCs have a functional UPR, which can be activated in response to ischemic stress. ATF6 loss of function (LOF) in CSCs, via RNAi or chemical inhibitor, yielded a basal decrease in cell viability and an increase in several differentiation markers, similar to the effect of dexamethasone differentiation stimulus. Increased ROS was also observed in an ATF6 LOF model. Strikingly, cotreatment with a chemical ROS inhibitor significantly rescued cell viability and reduced markers of differentiation in CSCs with reduced ATF6 function. These results suggest that CSCs require a basal level of ATF6 activity to maintain their proliferation and pluripotentcy in vitro and that this is mediated by the role of ATF6 in the mitigation of ROS. This is an important finding given that stem cell expansion in vitro is a critical step in the characterization of stem cells and their use in many therapeutic treatment strategies.

scholarly journals New insights into the unfolded protein response in stem cells

Oncotarget ◽  
2016 ◽  
Vol 7 (33) ◽  
pp. 54010-54027 ◽  
Author(s):  
Yanzhou Yang ◽  
Hoi Hung Cheung ◽  
JiaJie Tu ◽  
Kai Kei Miu ◽  
Wai Yee Chan
Keyword(s):  
Stem Cells ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response
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