Carotenoids play pivotal roles in vision as light filters and precursor of chromophore. Many vertebrates also display the colorful pigments as ornaments in bare skin parts and feathers. Proteins ...involved in the transport and metabolism of these lipids have been identified including class B scavenger receptors and carotenoid cleavage dioxygenases. Recent research implicates members of the Aster protein family, also known as GRAM domain‐containing (GRAMD), in carotenoid metabolism. These multi‐domain proteins facilitate the intracellular movement of carotenoids from their site of cellular uptake by scavenger receptors to the site of their metabolic processing by carotenoid cleavage dioxygenases. We provide a model how the coordinated interplay of these proteins and their differential expression establishes carotenoid distribution patterns and function in tissues, with particular emphasis on the human retina.
Carotenoid pigments play critical roles as colorants, light filters, and chromophores. A novel class of lipid transfer proteins, the Aster proteins (GRAM‐domain containing) were identified. We discuss how the differential expression of Aster proteins and beta‐carotene‐oxygenase 2 (BCO2) establish the unique carotenoid distribution patterns in the macula of the human retina.
Von Lintig discusses the study by Amengual et al which sheds new light onto the putative interaction between beta-carotene and cholesterol metabolism and is a potential gamechanger. To investigate ...the putative effects of dietary beta-carotene on cholesterol homeostasis, the researchers used the beta-carotene-oxygenase-1 (BCO1) knockout mice in their preclinical study. In the future, it will be important to replicate the clinical study in larger cohorts. However, the association between the non-HDL cholesterol concentrations and BCO1 genotype in the UP AMIGOS cohort is remarkable.
•Universal structural properties shared by CCO enzymes are described.•We propose working enzymatic mechanisms for CCO action.•Catalytic mechanisms of non-heme iron-mediated reactions by CCOs are ...discussed.•Some human hereditary diseases caused by genetic alternations in RPE65.
Carotenoids and their metabolic derivatives serve critical functions in both prokaryotic and eukaryotic cells, including pigmentation, photoprotection and photosynthesis as well as cell signaling. These organic compounds are also important for visual function in vertebrate and non-vertebrate organisms. Enzymatic transformations of carotenoids to various apocarotenoid products are catalyzed by a family of evolutionarily conserved, non-heme iron-containing enzymes named carotenoid cleavage oxygenases (CCOs). Studies have revealed that CCOs are critically involved in carotenoid homeostasis and essential for the health of organisms including humans. These enzymes typically display a high degree of regio- and stereo-selectivity, acting on specific positions of the polyene backbone located in their substrates. By oxidatively cleaving and/or isomerizing specific double bonds, CCOs generate a variety of apocarotenoid isomer products. Recent structural studies have helped illuminate the mechanisms by which CCOs mobilize their lipophilic substrates from biological membranes to perform their characteristic double bond cleavage and/or isomerization reactions. In this review, we aim to integrate structural and biochemical information about CCOs to provide insights into their catalytic mechanisms.
Vitamin A is distributed within the body to support chromophore synthesis in the eyes and retinoid signaling in most other tissues. Two pathways exist for the delivery of vitamin A: the extrinsic ...pathway transports dietary vitamin A in lipoproteins from intestinal enterocytes to tissues, while the intrinsic pathway distributes vitamin A from hepatic stores bound to serum retinol binding protein (RBP). Previously, the intestine-specific homeodomain transcription factor (ISX) and the RBP receptor STRA6 were identified as gatekeepers of these pathways; however, it is not clear how mutations in the corresponding genes affect retinoid homeostasis. Here, we used a genetic dissection approach in mice to examine the contributions of these proteins in select tissues. We observed that ISX deficiency increased utilization of both preformed and provitamin A. We found that increased storage of retinoids in peripheral tissues of ISX-deficient mice was dependent on STRA6 and induced by retinoid signaling. In addition, double-mutant mice exhibited a partial rescue of the Stra6 mutant ocular phenotype. This rescue came at the expense of a massive accumulation of vitamin A in other tissues, demonstrating that vitamin A is randomly distributed when present in excessive amounts. Remarkably, provitamin A supplementation of mutant mice induced the expression of the RBP receptor 2 in the liver and was accompanied by increased hepatic retinyl ester stores. Taken together, these findings indicate dynamic crosstalk between the delivery pathways for this essential nutrient and suggest that hepatic reuptake of vitamin A takes place when excessive amounts circulate in the blood.
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Vitamin A deficiency is a major public health problem in developing countries. Some studies also implicate a suboptimal vitamin A intake in certain parts of the population of the industrialized ...world. Provitamin A carotenoids such as β-carotene are the major source for retinoids (vitamin A and its derivatives) in the human diet. However, it is still controversial how much β-carotene intake is required and safe. An important contributor to this uncertainty is the lack of knowledge about the biochemical and molecular basis of β-carotene metabolism. Recently, key players of provitamin A metabolism have been molecularly identified and biochemically characterized. Studies in knockout mouse models showed that intestinal β-carotene absorption and conversion to retinoids is under negative feedback regulation that adapts this process to the actual requirement of vitamin A of the body. These studies also showed that in peripheral tissues a conversion of β-carotene occurs and affects retinoid-dependent physiologic processes. Moreover, these analyses provided a possible explanation for the adverse health effects of carotenoids by showing that a pathologic accumulation of these compounds can induce oxidative stress in mitochondria and cell signaling pathways related to disease. Genetic polymorphisms in identified genes exist in humans and also alter carotenoid homeostasis. Here, the advanced knowledge of β-carotene metabolism is reviewed, which provides a molecular framework for understanding the role of this important micronutrient in health and disease.
The critical role of retinoids (vitamin A and its derivatives) for vision, reproduction, and survival has been well established. Vitamin A is produced from dietary carotenoids such as β‐carotene by ...centric cleavage via the enzyme BCO1. The biochemical and molecular identification of a second structurally related β‐carotene metabolizing enzyme, BCO2, has led to a prolonged debate about its relevance in vitamin A biology. While BCO1 cleaves provitamin A carotenoids, BCO2 is more promiscuous and also metabolizes non‐provitamin A carotenoids such as zeaxanthin into long‐chain apo‐carotenoids. Herein we demonstrate, in cell lines, that human BCO2 is associated with the inner mitochondrial membrane. Different human BCO2 isoforms possess cleavable N‐terminal leader sequences critical for mitochondrial import. Subfractionation of murine hepatic mitochondria confirmed the localization of BCO2 to the inner mitochondrial membrane. Studies in BCO2‐knockout mice revealed that zeaxanthin accumulates in the inner mitochondrial membrane; in contrast, β‐carotene is retained predominantly in the cytoplasm. Thus, we provide evidence for a compartmentalization of carotenoid metabolism that prevents competition between BCO1 and BCO2 for the provitamin and the production of noncanonical β‐carotene metabolites.—Palczewski, G., Amengual, J., Hoppel, C. L., von Lintig, J., Evidence for compartmentalization of mammalian carotenoid metabolism. FASEB J. 28, 4457–4469 (2014). www.fasebj.org
All animals endowed with the ability to detect light through visual pigments must have evolved pathways in which dietary precursors for the involved chromophore are absorbed, transported, and ...metabolized. Knowledge about this metabolism has exponentially increased over the past decade. Genetic manipulation of animal models provided insights into the metabolic flow of these compounds through the body and in the eyes, unraveling their regulatory aspects and aberrant side reactions. The scheme that emerges reveals a common origin of key components for chromophore metabolism that have been adapted to the specific requirements of retinoid biology in different animal classes.
ABSTRACT
Exposure to light and accumulation of aberrant visual cycle by‐products causes stress in the retina. The physical and chemical properties of carotenoids may provide protection against such ...scenario. These pigments exist in retinas of many vertebrates, including humans. However, the absence of carotenoids in mice, the preferred ophthalmologic animal model, hindered molecular and biochemical examination of the pigments′ role in vision. We established a mouse model that accumulates significant amounts of carotenoids in the retina due to inactivating mutations in the Isx and Bco2 genes. We introduced a robust light damage protocol for the mouse retina using green (532 nm) and blue (405 nm) low‐energy lasers. We observed that blue but not green laser light treatment triggered the formation of aberrant retinaldehyde isomers in the retina. The production of these visual cycle by‐products was accompanied by morphologic damage in inferior parts of the mouse retina. Zeaxanthin supplementation of mice shielded retinoids from these photochemical modifications. These pigments also reduced the extent of the damage to the retina after the blue laser light insult. Thus, our study discovered a novel role of carotenoids in the visual cycle and indicated that vertebrates accumulate carotenoids to shield photoreceptors from short‐wavelength light‐ induced damage.—Widjaia‐Adhi, M. A. K., Ramkumar, S., von Lintig, J. Protective role of carotenoids in the visual cycle. 32, 6305–6315 (2018). www.fasebj.org
Scope
Beta‐carotene‐15,15′‐oxygenase (BCO1) and beta‐carotene‐9′,10′‐oxygenase (BCO2) metabolize lycopene to biologically active metabolites, which can ameliorate nonalcoholic fatty liver disease ...(NAFLD). We investigate the effects of tomato powder (TP containing substantial lycopene (2.3 mg/g)) on NAFLD development and gut microbiome in the absence of both BCO1 and BCO2 in mice.
Method and results
BCO1−/−/BCO2−/− double knockout mice were fed a high fat diet (HFD) alone (n = 9) or with TP feeding (n = 9) for 24 weeks. TP feeding significantly reduced pathological severity of steatosis and hepatic triglyceride levels in BCO1−/−/BCO2−/− mice (p < 0.04 vs HFD alone). This was associated with increased SIRT1 activity, nicotinamide phosphoribosyltransferase expression and AMP‐activated protein kinase phosphorylation, and subsequently decreased lipogenesis, hepatic fatty acid uptake, and increasing fatty acid β‐oxidation (p < 0.05). TP feeding significantly decreased mRNA expression of proinflammatory genes (tnf‐α, il‐1β, and il‐6) in both liver and mesenteric adipose tissue, which were associated with increased plasma adiponectin and hepatic adiponectin receptor‐2. Multiplexed 16S rRNA gene sequencing was performed using DNA extracted from cecum fecal samples. TP feeding increased microbial richness and decreased relative abundance of the genus Clostridium.
Conclusion
Dietary TP can inhibit NAFLD independent of carotenoid cleavage enzymes, potentially through increasing SIRT1 activity and adiponectin production and decreasing Clostridium abundance.
One of the consequences of the obesity epidemic is an increased prevalence of nonalcoholic fatty liver disease (NAFLD). This study demonstrates that dietary TP effectively inhibits high fat diet (HFD)‐induced NAFLD independent of carotenoid cleavage enzymes.
Vitamin A (VA) deficiency is a public health problem in some countries. Fortification, supplementation, and increased provitamin A consumption through biofortification are efficacious, but monitoring ...is needed due to risk of excessive VA intake when interventions overlap.
Two studies in 28–36-d-old male Mongolian gerbils simulated exposure to multiple VA interventions to determine the effects of provitamin A carotenoid consumption from biofortified maize and carrots and preformed VA fortificant on status.
Study 1 was a 2 × 2 × 2 factorial design (n = 85) with high-β-carotene maize, orange carrots, and VA fortification at 50% estimated gerbil needs, compared with white maize and white carrot controls. Study 2 was a 2 × 3 factorial design (n = 66) evaluating orange carrot and VA consumption through fortification at 100% and 200% estimated needs. Both studies utilized 2-wk VA depletion, baseline evaluation, 9-wk treatments, and liver VA stores by HPLC. Intestinal scavenger receptor class B member 1 (Scarb1), β-carotene 15,15′-dioxygenase (Bco1), β-carotene 9′,10′-oxygenase (Bco2), intestine-specific homeobox (Isx), and cytochrome P450 26A1 isoform α1 (Cyp26a1) expression was analyzed by qRT-PCR in study 2.
In study 1, liver VA concentrations were significantly higher in orange carrot (0.69 ± 0.12 μmol/g) and orange maize groups (0.52 ± 0.21 μmol/g) compared with baseline (0.23 ± 0.069 μmol/g) and controls. Liver VA concentrations from VA fortificant alone (0.11 ± 0.053 μmol/g) did not differ from negative control. In study 2, orange carrot significantly enhanced liver VA concentrations (0.85 ± 0.24 μmol/g) relative to baseline (0.43 ± 0.14 μmol/g), but VA fortificant alone (0.42 ± 0.21 μmol/g) did not. Intestinal Scarb1 and Bco1 were negatively correlated with increasing liver VA concentrations (P < 0.01, r2 = 0.25–0.27). Serum retinol concentrations did not differ.
Biofortified carrots and maize without fortification prevented VA deficiency in gerbils. During adequate provitamin A dietary intake, preformed VA intake resulted in excessive liver stores in gerbils, despite downregulation of carotenoid absorption and cleavage gene expression.
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