Vitamin D Promotes Protein Homeostasis and Longevity via the Stress Response Pathway Genes skn-1, ire-1, and xbp-1

Mark, Karla A.; Dumas, Kathleen J.; Bhaumik, Dipa; Schilling, Birgit; Davis, Sonnet S.; Oron, Tal; Sørensen, Dan; Lucanic, Mark; Brem, Rachel B.; Melov, Simon; Ramanathan, Arvind; Gibson, Bradford W.; Lithgow, Gordon J.

doi:10.1016/j.celrep.2016.09.086

Cited by 68 publications

(51 citation statements)

References 67 publications

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“…In humans, clinical studies suggest that VDR is widely expressed in liver inflammatory cells of chronic liver disease patients, and the expression level is negatively correlated to the severity of liver histology . Moreover, a recent study in C. elegans illustrated that dietary vitamin D supplementation promotes protein homeostasis and prevents aging‐associated accumulation of insoluble proteins . Accordingly, our findings verify that VDR signaling is required to maintain ER homeostasis in the liver.…”

Section: Discussionsupporting

confidence: 75%

“…(42) Moreover, a recent study in C. elegans illustrated that dietary vitamin D supplementation promotes protein homeostasis and prevents aging-associated accumulation of insoluble proteins. (43) Accordingly, our findings verify that VDR signaling is required to maintain ER homeostasis in the liver. Meanwhile, it is necessary to explore whether myeloid VDR signaling plays an essential role in hepatic response to other stress stimulators under both physiological and pathological conditions.…”

Section: Discussionsupporting

confidence: 66%

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Vitamin D Receptor Activation in Liver Macrophages Protects Against Hepatic Endoplasmic Reticulum Stress in Mice

et al. 2020

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Background and Aims Hepatic endoplasmic reticulum (ER) stress, whether triggered by intrinsic or extrinsic factors, can be resolved by the unfolded protein response (UPR). Sustained UPR activation leads to cell death and inflammatory response and contributes to liver disease progression. Hepatic tissue macrophages are key players in orchestrating liver inflammation, and ER stress can enhance macrophage activation. However, it is not well defined how the interplay between ER stress and inflammation is regulated during hepatic stress response. Approach and Results Here we demonstrate that vitamin D receptor (VDR) activation mitigates hepatic ER stress response, whereas VDR knockout mice undergo persistent UPR activation and apoptosis in response to chemical ER stress inducer. Moreover, VDR deficiency promotes hepatic macrophage infiltration and increases gene expression and systematic levels of proinflammatory cytokines, including interleukin (IL)‐1β, IL‐6, and tumor necrosis factor α. VDR expression is induced in hepatic macrophages by ER stress, and VDR plays a dual regulatory role in macrophages by protecting against ER stress and promoting anti‐inflammatory polarization. Co‐culture with VDR‐activated bone marrow–derived macrophages suppresses UPR target genes in primary hepatocytes treated with ER stress inducers. Thus, the immunomodulatory functions of VDR in macrophages are critical in hepatic ER stress resolution in mice. Conclusions VDR signaling in macrophages regulates a shift between proinflammatory and anti‐inflammatory activation during ER stress–induced inflammation to promote hepatic ER stress resolution.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionsupporting

confidence: 66%

Vitamin D Receptor Activation in Liver Macrophages Protects Against Hepatic Endoplasmic Reticulum Stress in Mice

et al. 2020

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“…Furthermore, vitamin D can exert powerful immunomodulatory actions to modify the immune response to injury during various diseases, including atherosclerosis [64,138], cancer [25], asthma [139], and stroke [50]. In particular, vitamin D can attenuate inflammatory responses and promote protein homeostasis via modulating the NF-κB and unfolded protein response (UPR) pathways, respectively [140,141]. In addition, vitamin D can regulate matrix homeostasis through the modulation of distinct matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) [142], consistent with its deficiency being critical in major cerebrovascular diseases, including brain aneurysms, cerebrovascular malformations, and stroke, where matrix destabilization is significant [118,143,144].…”

Section: Vitamin D Deficiency and Its Impact On Cerebrovascular Diseasesmentioning

confidence: 99%

Vitamin D Deficiency and the Risk of Cerebrovascular Disease

Kim

Perrelli

Ragni³

et al. 2020

Antioxidants

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Vitamin D deficiency has been clearly linked to major chronic diseases associated with oxidative stress, inflammation, and aging, including cardiovascular and neurodegenerative diseases, diabetes, and cancer. In particular, the cardiovascular system appears to be highly sensitive to vitamin D deficiency, as this may result in endothelial dysfunction and vascular defects via multiple mechanisms. Accordingly, recent research developments have led to the proposal that pharmacological interventions targeting either vitamin D deficiency or its key downstream effects, including defective autophagy and abnormal pro-oxidant and pro-inflammatory responses, may be able to limit the onset and severity of major cerebrovascular diseases, such as stroke and cerebrovascular malformations. Here we review the available evidence supporting the role of vitamin D in preventing or limiting the development of these cerebrovascular diseases, which are leading causes of disability and death all over the world.

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“…In addition to its known significance in bone and calcium homeostasis, vitamin D improves protein homeostasis and slows aging (Mark et al, 2016). The enzymes involved in conversion of 25(OH)D 3 to 1,25(OH) 2 D 3 are all present in the brain (Harms, Burne, Eyles, & McGrath, 2011).…”

Section: Introductionmentioning

confidence: 99%

Serum vitamin D in patients with mild cognitive impairment and Alzheimer's disease

et al. 2018

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ObjectivesTo determine the relevance of Mini‐Mental State Examination (MMSE), serum 25‐hydroxyvitamin D (25(OH)D3), and 1,25(OH)2D3 concentrations to mild cognitive impairment (MCI) and various stages of Alzheimer's disease (AD).Materials and MethodsThe study included 230 participants (>74 years) allocated to three main groups: 1‐healthy subjects (HS, n = 61), 2‐patients with MCI (n = 61), and 3‐ patients with Alzheimer's disease (AD) subdivided into three stages: mild (n = 41), moderate (n = 35), and severe AD (n = 32). The cognitive status was evaluated using MMSE. Serum 25 (OH)D3 (ng/ml) and 1,25(OH)2D3 concentrations (pg/ml) were determined by competitive radioimmunoassay.Results MMSE scores and 25(OH)D3 were decreased in MCI and all stages of the AD in both genders. MMSE variability was due to gender in HS (11%) and to 25(OH)D3 in MCI (15%) and AD (26%). ROC analysis revealed an outstanding property of MMSE in diagnosis of MCI (AUC, 0.906; CI 95%, 0.847–0.965; sensitivity 82%; specificity, 98%) and AD (AUC, 0.997; CI 95%, 0.992–1; sensitivity, 100%; specificity, 98%). 25(OH)D3 exhibited good property in MCI (AUC, 0.765; CI 95%, 0.681–0.849; sensitivity, 90%; specificity, 54%) and an excellent property in diagnosis of AD (AUC, 0.843; CI 95%, 0.782–0.904; sensitivity, 97%; specificity, 79%). Logistic analyses revealed that, in MCI, MMSE could predict (or classify correctly) with 97.6% accuracy (Wald, 15.22, β, −0.162; SE, 0.554; OR = 0.115:0.039–0.341; p = .0001), whereas 25(OH)D3 with 80% accuracy (Wald, 41,013; β, −0.213; SE, 0.033; OR = 0.808: 0.757–863; p = .0001). 25(OH)D3 was the only significant predictor for the severe AD and contributed to MMSE variability. Age and gender were significant predictors only in the moderate AD. In patients with MCI, 25(OH)D3 and 1,25(OH)2D3 were correlated men, but in case of the AD, they were correlated in women.Conclusions MMSE and serum 25(OH)D3 concentrations could be useful biomarkers for prediction and diagnosis of MCI and various stages of the AD. The results support the utility of vitamin D supplementation in AD therapy regimen.

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Vitamin D Promotes Protein Homeostasis and Longevity via the Stress Response Pathway Genes skn-1, ire-1, and xbp-1

Cited by 68 publications

References 67 publications

Vitamin D Receptor Activation in Liver Macrophages Protects Against Hepatic Endoplasmic Reticulum Stress in Mice

Vitamin D Receptor Activation in Liver Macrophages Protects Against Hepatic Endoplasmic Reticulum Stress in Mice

Vitamin D Deficiency and the Risk of Cerebrovascular Disease

Serum vitamin D in patients with mild cognitive impairment and Alzheimer's disease

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