7 research outputs found
The ATF6-Met [67] Val substitution is associated with increased plasma cholesterol levels
Objective— Activating transcription factor 6 (ATF6) is a sensor of the endoplasmic reticulum stress response and regulates expression of several key lipogenic genes. We used a 2-stage design to investigate whether ATF6 polymorphisms are associated with lipids in subjects at increased risk for cardiovascular disease (CVD). Methods and Results— In stage 1, 13 tag-SNPs were tested for association in Dutch samples ascertained for familial combined hyperlipidemia (FCHL) or increased risk for CVD (CVR). In stage 2, we further investigated the SNP with the strongest association from stage 1, a Methionine/Valine substitution at amino-acid 67, in Finnish FCHL families and in subjects with CVR from METSIM, a Finnish population-based cohort. The combined analysis of both stages reached region-wide significance (P=9x10–4), but this association was not seen in the entire METSIM cohort. Our functional analysis demonstrated that Valine at position 67 augments ATF6 protein and its targets Grp78 and Grp94 as well as increases luciferase expression through Grp78 promoter. Conclusions— A common nonsynonymous variant in ATF6 increases ATF6 protein levels and is associated with cholesterol levels in subjects at increased risk for CVD, but this association was not seen in a population-based cohort. Further replication is needed to confirm the role of this variant in lipids. We report the association of the ATF6-methionine [67]valine amino-acid substitution with plasma cholesterol levels. Association analyses in 2674 subjects and functional data suggest that the ATF6 gene may influence cholesterol levels in subjects at increased risk to develop cardiovascular disease
Recommended from our members
mTORC1 inhibition impairs activation of the unfolded protein response and induces cell death during ER stress in cardiomyocytes
The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of protein synthesis that senses and responds to a variety of stimuli to coordinate cellular metabolism with environmental conditions. To ensure that protein synthesis is inhibited during unfavorable conditions, translation is directly coupled to the sensing of cellular protein homeostasis. Thus, translation is attenuated during endoplasmic reticulum (ER) stress by direct inhibition of the mTORC1 pathway. However, residual mTORC1 activity is maintained during prolonged ER stress, which is thought to be involved in translational reprogramming and adaption to ER stress. By analyzing the dynamics of mTORC1 regulation during ER stress, we unexpectedly found that mTORC1 is transiently activated in cardiomyocytes within minutes at the onset of ER stress before being inhibited during chronic ER stress. This dynamic regulation of mTORC1 appears to be mediated, at least in part, by ATF6, as its activation was sufficient to induce the biphasic control of mTORC1. We further showed that protein synthesis remains dependent on mTORC1 throughout the ER stress response and that mTORC1 activity is essential for posttranscriptional induction of several unfolded protein response genes. Pharmacological inhibition of mTORC1 increased cell death during ER stress, indicating that the mTORC1 pathway serves adaptive functions during ER stress in cardiomyocytes potentially by controlling the expression of protective unfolded protein response genes. NEW & NOTEWORTHY Cells coordinate translation rates with protein quality control to ensure that protein synthesis is initiated primarily when proper protein folding can be achieved. Long-term activity of the unfolded protein response is therefore associated with an inhibition of mTORC1, a central regulator of protein synthesis. Here, we found that mTORC1 is transiently activated early in response to ER stress before it is inhibited. Importantly, partial mTORC1 activity remained essential for the upregulation of adaptive unfolded protein response genes and cell survival in response to ER stress. Our data reveal a complex regulation of mTORC1 during ER stress and its involvement in the adaptive unfolded protein response. Copyright © 2023 The Authors.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]