(off)Targeting UPR signaling: the race toward intervening ER proteostasis

Pérez-Arancibia, Rodrigo; Rivas, Alexis; Hetz, Claudio

doi:10.1080/14728222.2018.1420169

Cited by 8 publications

(5 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The native ER protein, ATF6, controls one of the three branches of the UPR and has been shown to be assisted by EDEM1. ATF6 is selectively translated by the phosphorylation of eIF2α and participates in a feedback loop by inducing expression of eIF2α phosphatase, GADD34 [ 43 ]. Transcript levels of Atf6 were increased in PHF livers at E14.5, but not at E18.5 ( Supplemental Table S10 ).…”

Section: Resultsmentioning

confidence: 99%

Paternal obesity induces placental hypoxia and sex-specific impairments in placental vascularization and offspring metabolism

Jazwiec

Patterson

Ribeiro

et al. 2022

Biology of Reproduction

View full text Add to dashboard Cite

Paternal obesity predisposes offspring to metabolic dysfunction, but the underlying mechanisms remain unclear. We investigated whether this metabolic dysfunction is associated with changes in placental vascular development and is fueled by endoplasmic reticulum (ER) stress-mediated changes in fetal hepatic development. We also determined whether paternal obesity indirectly affects the in utero environment by disrupting maternal metabolic adaptations to pregnancy. Male mice fed a standard chow or high fat diet (60%kcal fat) for 8–10 weeks were time-mated with female mice to generate pregnancies and offspring. Glucose tolerance was evaluated in dams at mid-gestation (embryonic day (E) 14.5) and late gestation (E18.5). Hypoxia, angiogenesis, endocrine function, macronutrient transport, and ER stress markers were evaluated in E14.5 and E18.5 placentae and/or fetal livers. Maternal glucose tolerance was assessed at E14.5 and E18.5. Metabolic parameters were assessed in offspring at ~60 days of age. Paternal obesity did not alter maternal glucose tolerance but induced placental hypoxia and altered placental angiogenic markers, with the most pronounced effects in female placentae. Paternal obesity increased ER stress-related protein levels (ATF6 and PERK) in the fetal liver and altered hepatic expression of gluconeogenic factors at E18.5. Offspring of obese fathers were glucose intolerant and had impaired whole-body energy metabolism, with more pronounced effects in female offspring. Metabolic deficits in offspring due to paternal obesity may be mediated by sex-specific changes in placental vessel structure and integrity that contribute to placental hypoxia and may lead to poor fetal oxygenation and impairments in fetal metabolic signaling pathways in the liver.

show abstract

Section: Resultsmentioning

confidence: 99%

Paternal obesity induces placental hypoxia and sex-specific impairments in placental vascularization and offspring metabolism

Jazwiec

Patterson

Ribeiro

et al. 2022

Biology of Reproduction

View full text Add to dashboard Cite

show abstract

“…One strategy with encouraging results so far for several neurodegenerative diseases is to target the UPR pathways (Shenkman et al, 2015; Xiang et al, 2016; Pérez-Arancibia et al, 2017). PERK, one of the three UPR sensors, is an interesting and promising target (recently reviewed in Halliday et al, 2017a; McQuiston and Diehl, 2017; Ohno, 2017; Hughes and Mallucci, 2018; Taalab et al, 2018).…”

Section: Therapeutic Approaches For Hdmentioning

confidence: 99%

Protein Misfolding and ER Stress in Huntington's Disease

Shacham

Sharma

Lederkremer

2019

Front. Mol. Biosci.

View full text Add to dashboard Cite

Increasing evidence in recent years indicates that protein misfolding and aggregation, leading to ER stress, are central factors of pathogenicity in neurodegenerative diseases. This is particularly true in Huntington's disease (HD), where in contrast with other disorders, the cause is monogenic. Mutant huntingtin interferes with many cellular processes, but the fact that modulation of ER stress and of the unfolded response pathways reduces the toxicity, places these mechanisms at the core and gives hope for potential therapeutic approaches. There is currently no effective treatment for HD and it has a fatal outcome a few years after the start of symptoms of cognitive and motor impairment. Here we will discuss recent findings that shed light on the mechanisms of protein misfolding and aggregation that give origin to ER stress in neurodegenerative diseases, focusing on Huntington's disease, on the cellular response and on how to use this knowledge for possible therapeutic strategies.

show abstract

“…ATF6 is selectively translated by the phosphorylation of eIF2α and participates on a feedback loop by inducing the expression of the eIF2α phosphatase, GADD34. 43 While transcript levels of Ppp1r15a, the gene that encodes for GADD34, were not changed in PHF liver at E14.5 or E18.5 (data not shown), transcript levels of Edem1 were increased in female PHF liver compared to female CON liver at E14.5 (P Int = 0.0418, P Diet = 0.0095, P = 0.0112; Fig. 8I) but not at E18.5.…”

Section: Paternal Obesity Activates the Upr In The Fetal Livermentioning

confidence: 87%

Paternal obesity results in placental hypoxia and sex-specific impairments in placental vascularization and offspring metabolic function

Jazwiec

Patterson

Ribeiro

et al. 2021

Preprint

View full text Add to dashboard Cite

Paternal obesity predisposes offspring to metabolic dysfunction, but the underlying mechanisms remain unclear. We investigated whether paternal obesity-induced offspring metabolic dysfunction is associated with placental endoplasmic reticulum (ER) stress and impaired vascular development. We determined whether offspring glucose intolerance is fueled by ER stress-mediated changes in fetal hepatic development. Furthermore, we also determined whether paternal obesity may indirectly affect in utero development by disrupting maternal metabolic adaptations to pregnancy. Male mice fed a standard chow diet (CON; 17% kcal fat) or high fat diet (PHF; 60% kcal fat) for 8-10 weeks were time-mated with control female mice to generate pregnancies and offspring. Glucose tolerance in pregnant females was evaluated at mid-gestation (embryonic day (E) 14.5) and term gestation (E18.5). At E14.5 and E18.5, fetal liver and placentae were collected, and markers of hypoxia, angiogenesis, endocrine function, and macronutrient transport, and unfolded protein response (UPR) regulators were evaluated to assess ER stress. Young adult offspring glucose tolerance and metabolic parameters were assessed at ~60 days of age. Paternal obesity did not alter maternal glucose tolerance or placental lactogen in pregnancy but did induce placental hypoxia, ER stress, and altered placental angiogenesis. This effect was most pronounced in placentae associated with female fetuses. Consistent with this, paternal obesity also activated the ATF6 and PERK branches of the UPR in fetal liver and altered hepatic expression of gluconeogenic factors at E18.5. Adult offspring of obese fathers showed glucose intolerance and impaired whole-body energy metabolism, particularly in female offspring. Thus, paternal obesity programs sex-specific adverse placental structural and functional adaptations and alters fetal hepatic development via ER stress-induced pathways. These changes likely underpin metabolic deficits in adult offspring.

show abstract

(off)Targeting UPR signaling: the race toward intervening ER proteostasis

Cited by 8 publications

References 15 publications

Paternal obesity induces placental hypoxia and sex-specific impairments in placental vascularization and offspring metabolism

Paternal obesity induces placental hypoxia and sex-specific impairments in placental vascularization and offspring metabolism

Protein Misfolding and ER Stress in Huntington's Disease

Paternal obesity results in placental hypoxia and sex-specific impairments in placental vascularization and offspring metabolic function

Contact Info

Product

Resources

About