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Xanthophylls Modulate Palmitoylation of Mammalian β-Carotene Oxygenase 2.

ABSTRACT: An extensive body of work has documented the antioxidant role of xanthophylls (lutein and zeaxanthin) in human health and specifically how they provide photoprotection in human vision. More recently, evidence is emerging for the transcriptional regulation of antioxidant response by lutein/lutein cleavage products, similar to the role of β-carotene cleavage products in the modulation of retinoic acid receptors. Supplementation with xanthophylls also provides additional benefits for the prevention of age-related macular degeneration (AMD) and attenuation of Alzheimer's disease symptoms. Mammalian β-carotene oxygenase 2 (BCO2) asymmetrically cleaves xanthophylls as well as β-carotene in vitro. We recently demonstrated that mouse BCO2 (mBCO2) is a functionally palmitoylated enzyme and that it loses palmitoylation when cells are treated with β-carotene. The mouse enzyme is the easiest model to study mammalian BCO2 because it has only one isoform, unlike human BCO2 with several major isoforms with various properties. Here, we used the same acyl-RAC methodology and confocal microscopy to elucidate palmitoylation and localization status of mBCO2 in the presence of xanthophylls. We created large unilamellar vesicle-based nanocarriers for the successful delivery of xanthophylls into cells. We demonstrate here that, upon treatment with low micromolar concentration of lutein (0.15 µM), mBCO2 is depalmitoylated and shows partial nuclear localization (38.00 ± 0.04%), while treatment with zeaxanthin (0.45 µM) and violaxanthin (0.6 µM) induces depalmitoylation and protein translocation from mitochondria to a lesser degree (20.00 ± 0.01% and 35.00 ± 0.02%, respectively). Such a difference in the behavior of mBCO2 toward various xanthophylls and its translocation into the nucleus in the presence of various xanthophylls suggests a possible mechanism for transport of lutein/lutein cleavage products to the nucleus to affect transcriptional regulation.

SUBMITTER: Uppal S

PROVIDER: S-EPMC8000801 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPlasma cholesterol is one of the strongest risk factors associated with the development of atherosclerotic cardiovascular disease (ASCVD) and myocardial infarction. Human studies suggest that elevated plasma β-carotene is associated with reductions in circulating cholesterol and the risk of myocardial infarction. The molecular mechanisms underlying these observations are unknown.ObjectiveThe objective of this study was to determine the impact of dietary β-carotene and the activity of β-carotene oxygenase 1 (BCO1), which is the enzyme responsible for the conversion of β-carotene to vitamin A, on circulating cholesterol concentration.MethodsIn our preclinical study, we compared the effects of a 10-d intervention with a diet containing 50 mg/kg of β-carotene on plasma cholesterol in 5-wk-old male and female C57 Black 6 wild-type and congenic BCO1-deficient mice. In our clinical study, we aimed to determine whether 5 common small nucleotide polymorphisms located in the BCO1 locus affected serum cholesterol concentrations in a population of young Mexican adults from the Universities of San Luis Potosí and Illinois: A Multidisciplinary Investigation on Genetics, Obesity, and Social-Environment (UP AMIGOS) cohort.ResultsUpon β-carotene feeding, Bco1-/- mice accumulated >20-fold greater plasma β-carotene and had ∼30 mg/dL increased circulating total cholesterol (P < 0.01) and non-HDL cholesterol (P < 0.01) than wild-type congenic mice. Our results in the UP AMIGOS cohort show that the rs6564851 allele of BCO1, which has been linked to BCO1 enzymatic activity, was associated with a reduction in 10 mg/dL total cholesterol concentrations (P = 0.009) when adjusted for vitamin A and carotenoid intakes. Non-HDL-cholesterol concentration was also reduced by 10 mg/dL when the data were adjusted for vitamin A and total carotenoid intakes (P = 0.002), or vitamin A and β-carotene intakes (P = 0.002).ConclusionsOverall, our results in mice and young adults show that BCO1 activity impacts circulating cholesterol concentration, linking vitamin A formation with the risk of developing ASCVD.

Project description:Low-grade inflammation is a critical pathological factor contributing to the development of metabolic disorders. β-carotene oxygenase 2 (BCO2) was initially identified as an enzyme catalyzing carotenoids in the inner mitochondrial membrane. Mutations in BCO2 are associated with inflammation and metabolic disorders in humans, yet the underlying mechanisms remain unknown. Here, we used loss-of-function approaches in mice and cell culture models to investigate the role of BCO2 in inflammation and metabolic dysfunction. We demonstrated decreases in BCO2 mRNA and protein levels and suppression of mitochondrial respiratory complex I proteins and mitochondrial superoxide dismutase levels in the liver of type 2 diabetic human subjects. Deficiency of BCO2 caused disruption of assembly of the mitochondrial respiratory supercomplexes, such as supercomplex III2+IV in mice, and overproduction of superoxide radicals in primary mouse embryonic fibroblasts. Further, deficiency of BCO2 increased protein carbonylation and populations of natural killer cells and M1 macrophages, and decreased populations of T cells, including CD4+ and/or CD8+ in the bone marrow and white adipose tissues. Elevation of plasma inflammatory cytokines and adipose tissue hypertrophy and inflammation were also characterized in BCO2 deficient mice. Moreover, BCO2 deficient mice were more susceptible to high-fat diet-induced obesity and hyperglycemia. Double knockout of BCO2 and leptin receptor genes caused a significantly greater elevation of the fasting blood glucose level in mice at 4 weeks of age, compared to the age- and sex-matched leptin receptor knockout. Finally, administration of Mito-TEMPO, a mitochondrial specific antioxidant attenuated systemic low-grade inflammation induced by BCO2 deficiency. Collectively, these findings suggest that BCO2 is essential for mitochondrial respiration and metabolic homeostasis in mammals. Loss or decreased expression of BCO2 leads to mitochondrial oxidative stress, low-grade inflammation, and the subsequent development of metabolic disorders.

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Xanthophylls Modulate Palmitoylation of Mammalian β-Carotene Oxygenase 2.

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