Tissue Changes Following Deprivation of Fat-Soluble a Vitamin.

Wolbach, Burt; Howe, Percy R.

doi:10.1111/j.1753-4887.1978.tb03675.x

Cited by 70 publications

(66 citation statements)

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“…During the heyday of nutritional vitamin research, it did not go unnoticed that many pathophysiological manifestations of vitamin A deficiency in animals and humans could not be corrected with retinoic acid but required vitamin A to restore health. Although several organs were affected (42), no organelle or molecular targets were recognized until researchers who explored the potential of retinoids for apoptosis induction focused on the mitochondrion. Most often the proapoptotic or necrotic outcomes were linked to the extended production of damaging levels of reactive oxygen species (9,13,43).…”

Section: Discussionmentioning

confidence: 99%

Control of oxidative phosphorylation by vitamin A illuminates a fundamental role in mitochondrial energy homoeostasis

et al. 2009

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The physiology of two metabolites of vitamin A is understood in substantial detail: retinaldehyde functions as the universal chromophore in the vertebrate and invertebrate eye; retinoic acid regulates a set of vertebrate transcription factors, the retinoic acid receptor superfamily. The third member of this retinoid triumvirate is retinol. While functioning as the precursor of retinaldehyde and retinoic acid, a growing body of evidence suggests a far more fundamental role for retinol in signal transduction. Here we show that retinol is essential for the metabolic fitness of mitochondria. When cells were deprived of retinol, respiration and ATP synthesis defaulted to basal levels. They recovered to significantly higher energy output as soon as retinol was restored to physiological concentration, without the need for metabolic conversion to other retinoids. Retinol emerged as an essential cofactor of protein kinase Cdelta (PKCdelta), without which this enzyme failed to be activated in mitochondria. Furthermore, retinol needed to physically bind PKCdelta, because mutation of the retinol binding site rendered PKCdelta unresponsive to Rol, while retaining responsiveness to phorbol ester. The PKCdelta/retinol complex signaled the pyruvate dehydrogenase complex for enhanced flux of pyruvate into the Krebs cycle. The baseline response was reduced in vitamin A-deficient lecithin:retinol acyl transferase-knockout mice, but this was corrected within 3 h by intraperitoneal injection of vitamin A; this suggests that vitamin A is physiologically important. These results illuminate a hitherto unsuspected role of vitamin A in mitochondrial bioenergetics of mammals, acting as a nutritional sensor. As such, retinol is of fundamental importance for energy homeostasis. The data provide a mechanistic explanation to the nearly 100-yr-old question of why vitamin A deficiency causes so many pathologies that are independent of retinoic acid action.

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Section: Discussionmentioning

confidence: 99%

Control of oxidative phosphorylation by vitamin A illuminates a fundamental role in mitochondrial energy homoeostasis

et al. 2009

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“…3 Retinoic acid is essential for the maintenance of normal epithelial differentiation and its depletion causes epithelial cell proliferation and loss of differentiation, thereby inducing neoplastic manifestations in the normal epithelium. [4][5][6] Therefore, the potential involvement of AKR1B10 in the process of carcinogenesis is intriguing.…”

Section: Introductionmentioning

confidence: 99%

Aldo‐keto reductase family 1 member B10 is associated with hepatitis B virus‐related hepatocellular carcinoma risk

Mori

Genda

Ichida

et al. 2016

Hepatology Research

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Aim: Recent reports have indicated that aldo-keto reductase family 1 member B10 (AKR1B10), a cancer-related oxidoreductase, was upregulated in some chronic liver diseases. However, few studies have reported AKR1B10 expression in chronic hepatitis B virus (HBV)-infected patients. The aim of the present study was to analyze AKR1B10 expression and its relevance on hepatocellular carcinoma (HCC) development in patients with chronic HBV infection.Methods: Expression of AKR1B10 in the liver of 119 chronic HBV-infected patients was assessed and quantified immunohistochemically. A multivariate Cox model was used to estimate the hazard ratios of AKR1B10 expression for HCC development. The cumulative incidences of HCC were evaluated using Kaplan-Meier analysis.Results: Expression of AKR1B10 in the study cohort ranged from 0% to 84%. During the median follow-up time (6.2 years), 13 patients developed HCC. Multivariate analysis revealed that high AKR1B10 expression (≥15%) was an independent risk factor for HCC (hazard ratio, 10.8; 95% confidence interval, 3.0-38.6; P < 0.001). The 5-year cumulative incidences of HCC were 20.6% and 2.6% in patients with high and low AKR1B10 expression, respectively (P < 0.001). Patients with high AKR1B10 expression had significantly higher alanine aminotransferase levels during follow-up than those with low expression, even though antiviral treatment decreased HBV-DNA levels in both groups. Conclusion:Chronic HBV-infected patients with high hepatic AKR1B10 expression had an increased risk of HCC development. This suggests that AKR1B10 upregulation might play a role in the early stages of HBV-related hepatocarcinogenesis.

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“…Retinoic acid receptors (RARs) are the main mediators of the biologic effects of vitamin A, with a long established essential role in the maintenance of the differentiated state of epithelial tissues [1]. More recently, retinoic acid (RA) and other RAR agonists were found to be growth inhibitory for cancer cell lines in vitro [2-7], in carcinogen-induced rodent mammary cancer models, [8-10] and in xenograft models of human cancer cell [11-13].…”

Section: Introductionmentioning

confidence: 99%

RARα1 control of mammary gland ductal morphogenesis and wnt1-tumorigenesis

et al. 2010

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IntroductionRetinoic acid signaling pathways are disabled in human breast cancer suggesting a controlling role in normal mammary growth that might be lost in tumorigenesis. We tested a single receptor isotype, RARα1 (retinoic acid receptor isotype alpha, isoform 1), for its role in mouse mammary gland morphogenesis and mouse mammary tumor virus (MMTV)-wingless-related MMTV integration site 1 (wnt1)-induced oncogenesis.MethodsThe role of RARα1 in mammary morphogenesis was tested in RARα1-knockout (KO) mice and in mammary tumorigenesis in bi-genic (RARα1/KO crossed with MMTV-wnt1) mice. We used whole mounts analysis, stem cells/progenitor quantification, mammary gland repopulation, quantitative polymerase chain reaction (Q-PCR), test of tumor-free survival, tumor fragments and cell transplantation.ResultsIn two genetic backgrounds (129/Bl-6 and FVB) the neo-natal RARα1/KO-mammary epithelial tree was two-fold larger and the pubertal tree had two-fold more branch points and five-fold more mature end buds, a phenotype that was predominantly epithelial cell autonomous. The stem/progenitor compartment of the RARα1/KO mammary, defined as CD24low/ALDHhigh activity was increased by a median 1.7-fold, but the mammary stem cell (MaSC)-containing compartment, (CD24low/CD29high), was larger (approximately 1.5-fold) in the wild type (wt)-glands, and the mammary repopulating ability of the wt-gland epithelium was approximately two-fold greater. In MMTV-wnt1 transgenic glands the progenitor (CD24low/ALDHhigh activity) content was 2.6-fold greater than in the wt and was further increased in the RARα1/KO-wnt1 glands. The tumor-free survival of RARα1/KO-wnt1 mice was significantly (P = 0.0002, Kaplan Meier) longer, the in vivo growth of RARα1/KO-wnt1 transplanted tumor fragments was significantly (P = 0.01) slower and RARα1/KO-wnt1 tumors cell suspension produced tumors after much longer latency.ConclusionsIn vitamin A-replete mice, RARα1 is required to maintain normal mammary morphogenesis, but paradoxically, also efficient tumorigenesis. While its loss increases the density of the mammary epithelial tree and the content of luminal mammary progenitors, it appears to reduce the size of the MaSC-containing compartment, the mammary repopulating activity, and to delay significantly the MMTV-wnt1-mammary tumorigenesis. Whether the delay in tumorigenesis is solely due to a reduction in wnt1 target cells or due to additional mechanisms remains to be determined. These results reveal the intricate nature of the retinoid signaling pathways in mammary development and carcinogenesis and suggest that a better understanding will be needed before retinoids can join the armament of effective anti-breast cancer therapies.

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Tissue Changes Following Deprivation of Fat-Soluble a Vitamin.

Cited by 70 publications

References 0 publications

Control of oxidative phosphorylation by vitamin A illuminates a fundamental role in mitochondrial energy homoeostasis

Control of oxidative phosphorylation by vitamin A illuminates a fundamental role in mitochondrial energy homoeostasis

Aldo‐keto reductase family 1 member B10 is associated with hepatitis B virus‐related hepatocellular carcinoma risk

RARα1 control of mammary gland ductal morphogenesis and wnt1-tumorigenesis

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