Vitamin A and the epigenome

Dadon, Shimrit Bar-El; Reifen, Ram

doi:10.1080/10408398.2015.1060940

Cited by 89 publications

(48 citation statements)

References 69 publications

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“…Vitamin A is an essential fat-soluble vitamin and adequate daily intake (~700–900 μg for humans) and hepatic storage (~80% in a healthy individual) are required to maintain plasma retinol levels around 2 μmol/L in humans (1–2 μmol/L in rodents) [ 2 , 3 ]. Vitamin A plays important physiological roles in vision, reproduction, growth, development, immunity, and metabolic programs [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. Most functions of vitamin A are mediated through the activation of ligand-activated transcription factors.…”

Section: Vitamin a Its Active Metabolites And Dietary Causes Of mentioning

confidence: 99%

Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD)

et al. 2017

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Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A’s functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs) and retinoid X receptors (RXRs).The liver plays a central role in vitamin A metabolism: (1) it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2) it produces retinol binding protein 4 (RBP4) that distributes vitamin A, as retinol, to peripheral tissues; and (3) it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs). In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 μmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH); it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M) is the most prominent heritable factor associated with NAFLD. Interestingly, PNPLA3 harbors retinyl ester hydrolase activity and PNPLA3-I148M is associated with low serum retinol level, but enhanced retinyl esters in the liver of NAFLD patients. Low circulating retinol in NAFLD may therefore not reflect true “vitamin A deficiency”, but rather disturbed vitamin A metabolism. Here, we summarize current knowledge about vitamin A metabolism in NAFLD and its putative role in the progression of liver disease, as well as the therapeutic potential of vitamin A metabolites.

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Section: Vitamin a Its Active Metabolites And Dietary Causes Of mentioning

confidence: 99%

Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD)

et al. 2017

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“…Nutritional factors which influence mineral homeostasis, differentiation of the osteoblasts and the immune system, such as vitamin D and vitamin A, have not previously been included in long-term studies of radiographic outcome in JIA [15, 16]. …”

Section: Introductionmentioning

confidence: 99%

Radiographic damage in hands and wrists of patients with juvenile idiopathic arthritis after 29 years of disease duration

et al. 2017

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BackgroundThere are few studies on radiographic outcome after long-term disease duration in juvenile idiopathic arthritis (JIA). We wanted to evaluate 29-year radiographic outcome in hands/wrists and predictors of damage in patients with long-term active JIA.MethodsPatients diagnosed from 1980 to 1985, who had active disease at 15-, 23- or 29-year follow-up and arthritis in the wrists during the disease course, were reexamined with radiographs of hands/wrists. We used the adapted version of the Sharp van der Heijde (aSvdH) score and Carpal Height Ratio (CHR) to evaluate radiographic outcome.ResultsSixty patients, mean age 38 years, were reexamined at median 29-year follow-up. 33 patients (55%) had an aSvdH score >0, median score was 4.0 (range 0–313), and 25% of the scores were high (≥53). Most patients with radiographic damage (88%) had both erosions and JSN. 52% of the patients had damage in the wrists, 43% in the MCP joints and 40% in the PIP joints.The CHR correlated strongly with the aSvdH. Both scores had high correlations with the Juvenile Arthritis Damage Index and the number of joints with limited range of motion (LROM) (rs = -0.688 to 0.743, p ≤ 0.001). The aSvdH correlated weakly with measures of disease activity.The number of joints with LROM, ESR and the HAQ disability score at 15 years and HLAB27 positivity predicted the aSvdH score and the CHR at 29-year follow-up.ConclusionsThe majority of patients with long-term active JIA had modest radiographic damage, but more frequently in wrists than in fingers. The radiographic scores correlated well with measures of disease damage. Restricted mobility in joints at 15 years was the most important predictor of radiographic damage at 29 years.

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“…Numerous studies have shown that ATRA and its agonists have preventive and therapeutic effects in various experimental kidney diseases by interfering with factors that contribute to renal damage (6,25,40,54). The physiological effects of ATRA and its receptors are mediated by modulating gene expression, which is a dynamic and orchestrated process involving association of receptors with a multitude of coregulators and epigenetic modulators (3,9,61).…”

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confidence: 99%

Inhibition of HDAC enhances STAT acetylation, blocks NF-κB, and suppresses the renal inflammation and fibrosis in Npr1 haplotype male mice

Kumar

Gogulamudi

Periasamy

et al. 2017

American Journal of Physiology-Renal Physiology

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Guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) plays a critical role in the regulation of blood pressure and fluid volume homeostasis. Mice lacking functional (coding for GC-A/NPRA) exhibit hypertension and congestive heart failure. However, the underlying mechanisms remain largely less clear. The objective of the present study was to determine the physiological efficacy and impact of all--retinoic acid (ATRA) and sodium butyrate (NaBu) in ameliorating the renal fibrosis, inflammation, and hypertension in gene-disrupted haplotype (1-copy; +/-) mice (50% expression levels of NPRA). Both ATRA and NaBu, either alone or in combination, decreased the elevated levels of renal proinflammatory and profibrotic cytokines and lowered blood pressure in mice compared with untreated controls. The treatment with ATRA-NaBu facilitated the dissociation of histone deacetylase (HDAC) 1 and 2 from signal transducer and activator of transcription 1 (STAT1) and enhanced its acetylation in the kidneys of mice. The acetylated STAT1 formed a complex with nuclear factor-κB (NF-κB) p65, thereby inhibiting its DNA-binding activity and downstream proinflammatory and profibrotic signaling cascades. The present results demonstrate that the treatment of the haplotype mice with ATRA-NaBu significantly lowered blood pressure and reduced the renal inflammation and fibrosis involving the interactive roles of HDAC, NF-κB (p65), and STAT1. The current findings will help in developing the molecular therapeutic targets and new treatment strategies for hypertension and renal dysfunction in humans.

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Vitamin A and the epigenome

Cited by 89 publications

References 69 publications

Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD)

Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD)

Radiographic damage in hands and wrists of patients with juvenile idiopathic arthritis after 29 years of disease duration

Inhibition of HDAC enhances STAT acetylation, blocks NF-κB, and suppresses the renal inflammation and fibrosis in Npr1 haplotype male mice

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