Endoplasmic reticulum oxidoreductin 1α mediates hepatic endoplasmic reticulum stress in homocysteine-induced atherosclerosis

Abstract

Endoplasmic reticulum (ER) stress is emerging as an important modulator of different pathological process and as a mechanism contributing to homocysteine (Hcy)-induced hepar injury. However, the molecular event that Hcyinduced ER stress in the hepar under the atherosclerosis background is currently unknown. Endoplasmic reticulum oxidoreductin 1a (ERO1a) plays a crucial role in maintaining ER stress function. In this study, we determined the expression of ERO1a in the hepar in hyperhomocysteinemia and the effect of ERO1a in hepacytes ER stress in the presence of Hcy. HHcy model was established by feeding the methionine diet in apolipoprotein-E-deficient (ApoE-/-) mice, and the hepatocytes were incubated with folate and different concentrations of Hcy. Our results showed that Hcy triggered ER stress characterized by an increased contents of glucoseregulated protein 78 (GRP78), protein kinase RNA-like ER kinase (PERK), activating transcription factor (ATF) 6 and X-box binding protein-1 (XBP-1). The ERO1a expressions in HHcy mice and Hcy-treated hepatocytes were decreased compared with those in ApoE-/-group and control hepacytes (P < 0.05), respectively. Knocking-down the expression of ERO1a with small-interfering RNA significantly augmented Hcy-induced ER stress. Meanwhile, the expressions of ER stress-related factor including GRP78, PERK, ATF6 and XBP-1, were significantly decreased when the ERO1a gene was over-expressed in hepacytes. Our results suggested that ERO1a may be involved in Hcy-induced hepar ER stress, and the inhibition of ERO1a expression can accelerate this process.

Homocysteine activates T cells by enhancing endoplasmic reticulum-mitochondria coupling and increasing mitochondrial respiration

“…In addition to the finding that Hcy reprograms mitochondrial metabolism, we found that Hcy also triggers ER stress in T cells, and inhibition of ER stress blocks Hcy-activated T cells, while stimulation of ER stress mimics this activation, suggesting that Hcy activates T cells by triggering ER stress. These results agree with the findings in vascular endothelial cells (Hossain et al, 2003 ), hepatocytes (Yang et al, 2014 ), neurons (Wei et al, 2014 ), and adipocytes (Li et al, 2013 ), where Hcy also causes ER stress. ER interacts with mitochondria forming dynamic networks across all cells to regulate multiple cellular processes (Bravo et al, 2011 ).…”

Expression of ERO1L in gastric cancer and its association with patient prognosis

“…The endoplasmic reticulum is the primary organelle of the cell and its primary function is to be responsible for the folding of protein and to maintain cell homeostasis (23). The stimulation of certain physiological, biochemical and pathological factors can lead to oxidative stress, so as to affect protein folding, the accumulation of unfolded protein and the misfolding of proteins in the endoplasmic reticulum, which leads to ERS (21,24). It was previously determined that ERS was prevalent in tumor tissues (25).…”

Hypermethylation of endoplasmic reticulum disulfide oxidase 1α leads to trophoblast cell apoptosis through endoplasmic reticulum stress in preeclampsia

“…DNA methylation is integrated together with DNA denaturation and bisulfite conversion processes into 1 step by the EZ DNA Methylation‐Gold TM Kit. Nested methylation‐specific PCR was used for the detection of methylation of ERO1α as previously described . The methylation primers used for methylmion specific PCR (MSP) are listed in Table .…”

“…It is reported that ER stress–mediated membrane expression of calreticulin/endoplasmic reticulum‐resident protein 57 (CRT/ERp57) induces cell apoptosis in drug‐resistant endometrial cancer cells. In our previous study, we found that ERO1α‐mediated ER stress is implicated in liver apoptosis in apolipoprotein‐E‐deficient (ApoE −/− ) mice …”