NFκB/Orai1 Facilitates Endoplasmic Reticulum Stress by Oxidative Stress in the Pathogenesis of Non-alcoholic Fatty Liver Disease

Zhang, Bingbing; Li, Ming; Zou, Ying; Guo, Han; Zhang, Bingdong; Xia, Cheng; Zhang, Hongyou; Yang, Wei; Xu, Chuang

doi:10.3389/fcell.2019.00202

Cited by 37 publications

(18 citation statements)

References 29 publications

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“…Zhang B and co-workers detected in rats fed with HFD increased blood levels of MDA and decreased blood levels of GSH, correlated with hepatic histopathological changes, observed after HE (hematoxylin eosin) staining [40].…”

Section: Resultsmentioning

confidence: 80%

“…Hypercaloric food (sugar and butter) administered daily to Wistar rats led to hepatic OS even after only 3 weeks. Zhang B and co-workers observed on a BRL-3A cell line that non-esterified fatty acids administration caused a significant decrease of GSH level and a great increase of MDA level [40]. Arya A and co-workers study results revealed increased plasma levels of MDA, ALT and NO metabolites and low levels of plasma SOD [41].…”

Section: Resultsmentioning

confidence: 94%

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Hypercaloric Diet and Vitamin E Intake

Radulescu¹,

Miricescu²,

Totan³

et al. 2019

Mat.Plast.

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PLGA (poly-lactic-co-glycolic acid) nanoparticles represent an important synthetic biocomponent that has the potential to be a promising carrier of drugs, proteins, nucleic acids, due to its biodegradability and minimal side effects. The aim of our study was to observe the antioxidant effect of vitamin E loaded in PLGA nanoparticles administered over a period of 3 weeks in Wistar rats treated with a hypercaloric diet. Glutathione (GSH) and malondiadehyde (MDA) biomarkers determined from liver lysate were analyzed to evaluate the oxidative stress (OS) induced by the hypercaloric diet. The results of our study revealed a statistically significant increase for GSH and vitamin E in group 2 of Wistar rats receiving hypercaloric diet and a daily dose of vitamin E versus group 1 (p[0.005). The antioxidant effect of vitamin E was also observed by the statistically significant decrease of MDA in group 2 of Wistar rats compared with group 1. The daily dose of vitamin E has improved the liver redox status of group 2 Wistar rats.

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Section: Resultsmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 94%

Hypercaloric Diet and Vitamin E Intake

Radulescu¹,

Miricescu²,

Totan³

et al. 2019

Mat.Plast.

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“…One potential pathway linking NEFAs and telomere length is oxidative stress. Higher circulating levels of NEFAs have been shown to promote de novo lipogenesis, causing abnormal hepatic lipid accumulation and oxidative stress [ 24 ]. Studies have also shown that reduction of NEFAs lowers oxidative stress [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Non-esterified fatty acids and telomere length in older adults: The Cardiovascular Health Study

et al. 2020

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Background Telomeres shorten as organisms age, placing limits on cell proliferation and serving as a marker of biological aging. Non-esterified fatty acids (NEFAs) are a key mediator of age-related metabolic abnormalities. We aimed to determine if NEFAs are associated with telomere length in community-living older adults. Material and methods We cross-sectionally studied 1648 participants of the Cardiovascular Health Study (CHS) who underwent concomitant telomere length measurement from a sample of 4715 participants who underwent measurement of circulating total fasting NEFAs in stored specimens from their 1992-3 clinic visit. We used linear regression and inverse probability weighting to model telomere length as a function of NEFAs with adjustment for age, gender, race, clinic, BMI, marital status, smoking status, alcohol intake, diabetes status, years of education, hypertension status, prevalent cardiovascular disease, C-reactive protein, total adiponectin, albumin, fetuin-A, fasting insulin, eGFR, total cholesterol, HDL-cholesterol, triglycerides, and general health status. Results Higher NEFAs were significantly associated with shorter telomere length, after adjusting for age, gender, race, and clinic site (β = −0.034; SE = 0.015; P = 0.02). Estimates remained similar in fully adjusted models where each SD of NEFA increment was associated with 0.042 kilobase (kb) pairs shorter telomere length (standard error = 0.016; P = 0.007); for comparison the coefficient for a single year of age in the same model was −0.017. These results were similar in strata of sex, and waist circumference although they tended to be strongest among participants in the youngest tertile of age (β = -0.079; SE = 0.029; P = 0.01). Conclusions In this population-based cohort of community-living elders, we observed a significant inverse association between NEFAs and telomere length. If confirmed, NEFAs may represent a promising target for interventions to slow biological aging.

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“…To induce downregulation of ORAI1, hepatocytes were transfected with 40 pM cattle ORAI1 small interfering (si)RNA (GenePharma, Shanghai, China) and a non-target siRNA (siRNA-mate, Shanghai GenePharma Co. Ltd., Shanghai, China) according to manufacturer's protocols (Zhang et al, 2019). Hepatocytes were cultured in 6-well plates for 48 h with growth medium.…”

Section: Cellular Manipulations Of Oxidative Stress and Orai1 Abundancementioning

confidence: 99%

Mitochondrial dysfunction and endoplasmic reticulum stress in calf hepatocytes are associated with fatty acid-induced ORAI calcium release-activated calcium modulator 1 signaling

Zhang

Yang

et al. 2020

Journal of Dairy Science

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The store-operated Ca 2+ entry (SOCE) moiety ORAI calcium release-activated calcium modulator 1 (ORAI1) located in the endoplasmic reticulum (ER) participates in key cellular functions such as protein folding, transport, and secretion, and lipid metabolism. We used an in vitro approach to test whether exogenous fatty acids alter ORAI1 signaling and to explore potential consequences on mitochondrial dysfunction and ER stress. First, hepatocytes isolated from 4 healthy female calves (1 d old, 40-50 kg) were challenged with a 1.2 mM mixture of oleic, linoleic, palmitic, stearic, and palmitoleic acids for 0.5, 1, 3, 6, 9, and 12 h to measure oxidative stress [intracellular reduced glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and hydrogen peroxide] and ER stress (protein abundance of PERK, IRE, ATF6, and GRP78). Concentrations of GSH and SOD decreased at 0.5 h, and MDA and hydrogen peroxide increased at 1 h; ER stress proteins increased at 6 h. To determine whether ER stress was caused by oxidative stress, primary calf hepatocytes were treated with the same 1.2 mM fatty acid mix or the reactive oxygen species (ROS) inhibitor N-acetylcysteine (NAC) for 6 h. We found that NAC prevented an increase in ER stress protein abundance. Next, the role of ORAI1 on ER stress was measured by transfecting hepatocytes with small interfering (si)ORAI1 or the ORAI1 inhibitor BTP2, followed by a challenge with 1.2 mM fatty acids for 3 h. Without inhibiting ORAI1, exogenous fatty acids upregulated ORAI1 mRNA and protein abundance, oxidative stress, ER stress proteins, and protein abundance of marker indicators of an opened mitochondrial permeability transition pore (mPTP). Inhibition with BPT2 or silencing via siO-RAI1 abrogated oxidative stress, including increased GSH concentration and SOD activity, decreased MDA, hydrogen peroxide, and ROS concentration; ER stress protein abundance was downregulated, and mitochondrial function was restored. Last, changes in markers of mPTP opening were evaluated by culturing hepatocytes for 6 h with the sarcoendoplasmic Ca 2+ ATPase inhibitor thapsigargin or the calcium ionophore ionomycin. We detected an increase in VDAC1, CLPP, and CypD protein abundance, all of which indicated opening of the mPTP. Overall, data from these in vitro studies suggest that ORAI1 mediates ER stress induced by high concentrations of fatty acids, in part through alleviating mitochondrial dysfunction caused by oxidative stress.

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NFκB/Orai1 Facilitates Endoplasmic Reticulum Stress by Oxidative Stress in the Pathogenesis of Non-alcoholic Fatty Liver Disease

Cited by 37 publications

References 29 publications

Hypercaloric Diet and Vitamin E Intake

Hypercaloric Diet and Vitamin E Intake

Non-esterified fatty acids and telomere length in older adults: The Cardiovascular Health Study

Mitochondrial dysfunction and endoplasmic reticulum stress in calf hepatocytes are associated with fatty acid-induced ORAI calcium release-activated calcium modulator 1 signaling

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