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Article ; Online: Aster la vista: Unraveling the biochemical basis of carotenoid homeostasis in the human retina.

Bandara, Sepalika / von Lintig, Johannes

BioEssays : news and reviews in molecular, cellular and developmental biology

2022 Volume 44, Issue 11, Page(s) e2200133

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Humans ; Carotenoids/chemistry ; Dioxygenases/metabolism ; Retina ; Homeostasis ; Lipids
Chemical Substances	Carotenoids (36-88-4) ; Dioxygenases (EC 1.13.11.-) ; Lipids
Language	English
Publishing date	2022-09-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	50140-2
ISSN	1521-1878 ; 0265-9247
ISSN (online)	1521-1878
ISSN	0265-9247
DOI	10.1002/bies.202200133
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Article ; Online: Eat Your Carrots! β-Carotene and Cholesterol Homeostasis.

von Lintig, Johannes

The Journal of nutrition

2020 Volume 150, Issue 8, Page(s) 2003–2005

MeSH term(s)	Cholesterol/metabolism ; Daucus carota/chemistry ; Homeostasis/drug effects ; Humans ; Lipid Metabolism/drug effects ; Retinoids/chemistry ; Retinoids/pharmacology ; beta Carotene/chemistry ; beta Carotene/metabolism ; beta Carotene/pharmacology
Chemical Substances	Retinoids ; beta Carotene (01YAE03M7J) ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2020-08-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218373-0
ISSN	1541-6100 ; 0022-3166
ISSN (online)	1541-6100
ISSN	0022-3166
DOI	10.1093/jn/nxaa189
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Article ; Online: Unraveling the mystery of ocular retinoid turnover: Insights from albino mice and the role of STRA6.

Ramkumar, Srinivasagan / Jastrzebska, Beata / Montenegro, Diego / Sparrow, Janet R / von Lintig, Johannes

The Journal of biological chemistry

2024 Volume 300, Issue 3, Page(s) 105781

Abstract: A delicate balance between photon absorption for vision and the protection of photoreceptors from light damage is pivotal for ocular health. This equilibrium is governed by the light-absorbing 11-cis-retinylidene chromophore of visual pigments, which, ... ...

Abstract	A delicate balance between photon absorption for vision and the protection of photoreceptors from light damage is pivotal for ocular health. This equilibrium is governed by the light-absorbing 11-cis-retinylidene chromophore of visual pigments, which, upon bleaching, transforms into all-trans-retinal and undergoes regeneration through an enzymatic pathway, named the visual cycle. Chemical side reactions of retinaldehyde during the recycling process can generate by-products that may result in a depletion of retinoids. In our study, we have clarified the crucial roles played by melanin pigmentation and the retinoid transporter STRA6 in preventing this loss and preserving the integrity of the visual cycle. Our experiments initially confirmed that consecutive green and blue light bleaching of isolated bovine rhodopsin produced 9-cis and 13-cis retinal. The same unusual retinoids were found in the retinas of mice exposed to intense light, with elevated concentrations observed in albino mice. Examining the metabolic fate of these visual cycle byproducts revealed that 9-cis-retinal, but not 13-cis-retinal, was recycled back to all-trans-retinal through an intermediate called isorhodopsin. However, investigations in Stra6 knockout mice unveiled that the generation of these visual cycle byproducts correlated with a light-induced loss of ocular retinoids and visual impairment. Collectively, our findings uncover important novel aspects of visual cycle dynamics, with implications for ocular health and photoreceptor integrity.
MeSH term(s)	Animals ; Cattle ; Mice ; Diterpenes ; Mice, Knockout ; Retina/metabolism ; Retinaldehyde/metabolism ; Retinoids/metabolism ; Vision, Ocular ; Membrane Proteins/metabolism
Chemical Substances	13-cis-retinal (472-86-6) ; Diterpenes ; Retinaldehyde (RR725D715M) ; Retinoids ; Stra6 protein, mouse ; Membrane Proteins
Language	English
Publishing date	2024-02-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2024.105781
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Article ; Online: Biology of carotenoids in mammals.

von Lintig, Johannes / Quadro, Loredana

Biochimica et biophysica acta. Molecular and cell biology of lipids

2020 Volume 1865, Issue 11, Page(s) 158754

MeSH term(s)	Animals ; Biology/trends ; Carotenoids/metabolism ; Mammals/metabolism
Chemical Substances	Carotenoids (36-88-4)
Language	English
Publishing date	2020-06-05
Publishing country	Netherlands
Document type	Editorial
ZDB-ID	60-7
ISSN	1879-2618 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2618 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbalip.2020.158754
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Article ; Online: ASTER-B regulates mitochondrial carotenoid transport and homeostasis.

Bandara, Sepalika / Moon, Jean / Ramkumar, Srinivasagan / von Lintig, Johannes

Journal of lipid research

2023 Volume 64, Issue 5, Page(s) 100369

Abstract: The scavenger receptor class B type 1 (SR-B1) facilitates uptake of cholesterol and carotenoids into the plasma membrane (PM) of mammalian cells. Downstream of SR-B1, ASTER-B protein mediates the nonvesicular transport of cholesterol to mitochondria for ... ...

Abstract	The scavenger receptor class B type 1 (SR-B1) facilitates uptake of cholesterol and carotenoids into the plasma membrane (PM) of mammalian cells. Downstream of SR-B1, ASTER-B protein mediates the nonvesicular transport of cholesterol to mitochondria for steroidogenesis. Mitochondria also are the place for the processing of carotenoids into diapocarotenoids by β-carotene oxygenase-2. However, the role of these lipid transport proteins in carotenoid metabolism has not yet been established. Herein, we showed that the recombinant StART-like lipid-binding domain of ASTER-A and B preferentially binds oxygenated carotenoids such as zeaxanthin. We established a novel carotenoid uptake assay and demonstrated that ASTER-B expressing A549 cells transport zeaxanthin to mitochondria. In contrast, the pure hydrocarbon β-carotene is not transported to the organelles, consistent with its metabolic processing to vitamin A in the cytosol by β-carotene oxygenase-1. Depletion of the PM from cholesterol by methyl-β-cyclodextrin treatment enhanced zeaxanthin but not β-carotene transport to mitochondria. Loss-of-function assays by siRNA in A549 cells and the absence of zeaxanthin accumulation in mitochondria of ARPE19 cells confirmed the pivotal role of ASTER-B in this process. Together, our study in human cell lines established ASTER-B protein as key player in nonvesicular transport of zeaxanthin to mitochondria and elucidated the molecular basis of compartmentalization of the metabolism of nonprovitamin A and provitamin A carotenoids in mammalian cells.
MeSH term(s)	Animals ; Humans ; Zeaxanthins/metabolism ; Carotenoids/metabolism ; beta Carotene/metabolism ; Cholesterol ; Mitochondria/metabolism ; Homeostasis ; Mammals/metabolism
Chemical Substances	Zeaxanthins ; Carotenoids (36-88-4) ; beta Carotene (01YAE03M7J) ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2023-04-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1016/j.jlr.2023.100369
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Article ; Online: Vitamin A deficiency compromises the barrier function of the retinal pigment epithelium.

Moon, Jean / Zhou, Gao / Jankowsky, Eckhard / von Lintig, Johannes

PNAS nexus

2023 Volume 2, Issue 6, Page(s) pgad167

Abstract: A major cause for childhood blindness worldwide is attributed to nutritional vitamin A deficiency. Surprisingly, the molecular basis of the ensuing retinal degeneration has not been well defined. Abundant expression of the retinoid transporter STRA6 in ... ...

Abstract	A major cause for childhood blindness worldwide is attributed to nutritional vitamin A deficiency. Surprisingly, the molecular basis of the ensuing retinal degeneration has not been well defined. Abundant expression of the retinoid transporter STRA6 in the retinal pigment epithelium (RPE) and homeostatic blood levels of retinol-binding protein delay vitamin A deprivation of the mouse eyes. Hence, genetic dissection of STRA6 makes mice susceptible to nutritional manipulation of ocular retinoid status. We performed RNA-seq analyses and complemented the data with tests of visual physiology, ocular morphology, and retinoid biochemistry to compare eyes with different vitamin A status. Mild ocular vitamin A deficiency decreased transcripts of photoreceptor transduction pathway-related genes and increased transcripts of oxidative stress pathways. The response was associated with impaired visual sensitivity and an accumulation of fluorescent debris in the retina. Severe vitamin A deficiency did not only impair visual perception but also decreased transcripts of genes encoding cell adhesion and cellular junction proteins. This response altered cell morphology, resulted in significant changes in transport pathways of small molecules, and compromised the barrier function of the RPE. Together, our analyses characterize the molecular events underlying nutritional blindness in a novel mouse model and indicate that breakdown of the outer blood-retinal barrier contributes to retinal degeneration and photoreceptor cell death in severe vitamin A deficiency.
Language	English
Publishing date	2023-05-19
Publishing country	England
Document type	Journal Article
ISSN	2752-6542
ISSN (online)	2752-6542
DOI	10.1093/pnasnexus/pgad167
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Article ; Online: Expression and biochemical analyses of proteins involved in the transport of carotenoids and retinoids.

Golczak, Marcin / Moise, Alexander R / von Lintig, Johannes

Methods in enzymology

2022 Volume 674, Page(s) 447–480

Abstract: Animals acquire carotenoids from the diet and convert them to retinoids. These lipids must be distributed in the body to support retinoid signaling in peripheral tissues and photoreceptor function in the eyes. However, the hydrophobicity of carotenoids ... ...

Abstract	Animals acquire carotenoids from the diet and convert them to retinoids. These lipids must be distributed in the body to support retinoid signaling in peripheral tissues and photoreceptor function in the eyes. However, the hydrophobicity of carotenoids and retinoids limit their diffusion in the aqueous environment of the body. Therefore, membrane proteins and cellular binding proteins transport these lipids between extra- and intracellular compartments and facilitate their metabolism. Mutations in genes encoding these transport proteins are associated with a wide spectrum of blinding disorders. Here, we describe approaches used by our laboratories that have proven successful in expressing these proteins and examining their biochemical properties in the test tube and in cell-based assays. These assays can be utilized for screening of small molecule modulators of their activities to correct pathologies associated with retinoid metabolism.
MeSH term(s)	Animals ; Carotenoids/metabolism ; Carrier Proteins/metabolism ; Lipid Metabolism ; Lipids ; Retinoids/metabolism
Chemical Substances	Carrier Proteins ; Lipids ; Retinoids ; Carotenoids (36-88-4)
Language	English
Publishing date	2022-06-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1557-7988
ISSN (online)	1557-7988
DOI	10.1016/bs.mie.2022.05.004
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Article ; Online: Carotenoid modifying enzymes in metazoans.

Moise, Alexander R / Bandara, Sepalika / von Lintig, Johannes

Methods in enzymology

2022 Volume 674, Page(s) 405–445

Abstract: Carotenoids constitute an essential dietary component of animals and other non-carotenogenic species which use these pigments in both their modified and unmodified forms. Animals utilize uncleaved carotenoids to mitigate light damage and oxidative stress ...

Abstract	Carotenoids constitute an essential dietary component of animals and other non-carotenogenic species which use these pigments in both their modified and unmodified forms. Animals utilize uncleaved carotenoids to mitigate light damage and oxidative stress and to signal fitness and health. Carotenoids also serve as precursors of apocarotenoids including retinol, and its retinoid metabolites, which carry out essential functions in animals by forming the visual chromophore 11-cis-retinaldehyde. Retinoids, such as all-trans-retinoic acid, can also act as ligands of nuclear hormone receptors. The fact that enzymes and biochemical pathways responsible for the metabolism of carotenoids in animals bear resemblance to the ones in plants and other carotenogenic species suggests an evolutionary relationship. We will explore some of the modes of transmission of carotenoid genes from carotenogenic species to metazoans. This apparent relationship has been successfully exploited in the past to identify and characterize new carotenoid and retinoid modifying enzymes. We will review approaches used to identify putative animal carotenoid enzymes, and we will describe methods used to functionally validate and analyze the biochemistry of carotenoid modifying enzymes encoded by animals.
MeSH term(s)	Animals ; Carotenoids/metabolism ; Plants/metabolism ; Retinaldehyde/metabolism ; Retinoids/metabolism
Chemical Substances	Retinoids ; Carotenoids (36-88-4) ; Retinaldehyde (RR725D715M)
Language	English
Publishing date	2022-06-22
Publishing country	United States
Document type	Journal Article
ISSN	1557-7988
ISSN (online)	1557-7988
DOI	10.1016/bs.mie.2022.05.005
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Article ; Online: Genetic deletion of Bco2 and Isx establishes a golden mouse model for carotenoid research.

Thomas, Linda D / Ramkumar, Srinivasagan / Golczak, Marcin / von Lintig, Johannes

Molecular metabolism

2023 Volume 73, Page(s) 101742

Abstract: Objective: Low plasma levels of carotenoids are associated with mortality and chronic disease states. Genetic studies in animals revealed that the tissue accumulation of these dietary pigments is associated with the genes encoding β-carotene oxygenase 2 ...

Abstract	Objective: Low plasma levels of carotenoids are associated with mortality and chronic disease states. Genetic studies in animals revealed that the tissue accumulation of these dietary pigments is associated with the genes encoding β-carotene oxygenase 2 (BCO2) and the scavenger receptor class B type 1 (SR-B1). Here we examined in mice how BCO2 and SR-B1 affect the metabolism of the model carotenoid zeaxanthin that serves as a macular pigment in the human retina. Methods: We used mice with a lacZ reporter gene knock-in to determine Bco2 expression patterns in the small intestine. By genetic dissection, we studied the contribution of BCO2 and SR-B1 to zeaxanthin uptake homeostasis and tissue accumulation under different supply conditions (50 mg/kg and 250 mg/kg). We determined the metabolic profiles of zeaxanthin and its metabolites in different tissues by LC-MS using standard and chiral columns. An albino Isx Results: We demonstrate that BCO2 is highly expressed in enterocytes of the small intestine. Genetic deletion of Bco2 led to enhanced accumulation of zeaxanthin, indicating that the enzyme serves as a gatekeeper of zeaxanthin bioavailability. Relaxing the regulation of SR-B1 expression in enterocytes by genetic deletion of the transcription factor ISX further enhanced zeaxanthin accumulation in tissues. We observed that the absorption of zeaxanthin was dose-dependent and identified the jejunum as the major zeaxanthin-absorbing intestinal region. We further showed that zeaxanthin underwent oxidation to ε,ε-3,3'-carotene-dione in mouse tissues. We detected all three enantiomers of the zeaxanthin oxidation product whereas the parent zeaxanthin only existed as (3R, 3'R)-enantiomer in the diet. The ratio of oxidized to parent zeaxanthin varied between tissues and was dependent on the supplementation dose. We further showed in an albino Isx Conclusions: We established the biochemical basis of zeaxanthin metabolism in mice and showed that tissue factors and abiotic stress affect the metabolism and homeostasis of this dietary lipid.
MeSH term(s)	Animals ; Humans ; Mice ; Carotenoids/metabolism ; Dioxygenases/genetics ; Dioxygenases/metabolism ; Disease Models, Animal ; Intestines ; Retina/metabolism ; Zeaxanthins/metabolism ; Transcription Factors/genetics
Chemical Substances	Bco2 protein, mouse (EC 1.14.99.-) ; Carotenoids (36-88-4) ; Dioxygenases (EC 1.13.11.-) ; Zeaxanthins ; Isx protein, mouse ; Transcription Factors
Language	English
Publishing date	2023-05-22
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2708735-9
ISSN	2212-8778 ; 2212-8778
ISSN (online)	2212-8778
ISSN	2212-8778
DOI	10.1016/j.molmet.2023.101742
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Article ; Online: Genetic tuning of β-carotene oxygenase-1 activity rescues cone photoreceptor function in STRA6-deficient mice.

Moon, Jean / Ramkumar, Srinivasagan / von Lintig, Johannes

Human molecular genetics

2022 Volume 32, Issue 5, Page(s) 798–809

Abstract: Rod and cone photoreceptors in the retina mediate dim light and daylight vision, respectively. Despite their distinctive functions, rod and cone visual pigments utilize the same vitamin A-derived chromophore. To sustain vision, vitamin A precursors must ... ...

Abstract	Rod and cone photoreceptors in the retina mediate dim light and daylight vision, respectively. Despite their distinctive functions, rod and cone visual pigments utilize the same vitamin A-derived chromophore. To sustain vision, vitamin A precursors must be acquired in the gut, metabolized, and distributed to the eyes. Deficiencies in this pathway in inherited ocular disease states deplete cone photoreceptors from chromophore and eventually lead to cell death, whereas the more abundant rod photoreceptors are less affected. However, pathways that support cone function and survival under such conditions are largely unknown. Using biochemical, histological, and physiological approaches, we herein show that intervention with β-carotene in STRA6-deficient mice improved chromophore supply to cone photoreceptors. Relieving the inherent negative feedback regulation of β-carotene oxygenase-1 activity in the intestine by genetic means further bolstered cone photoreceptor functioning in the STRA6-deficient eyes. A vitamin A-rich diet, however, did not improve cone photoreceptor function in STRA6-deficiency. We provide evidence that the beneficial effect of β-carotene on cones results from favorable serum kinetics of retinyl esters in lipoproteins. The respective alterations in lipoprotein metabolism maintained a steady supply of retinoids to the STRA6-deficient eyes, which ameliorated the competition for chromophore between rod and cone photoreceptors. Together, our study elucidates a cone photoreceptor-survival pathway and unravels an unexpected metabolic connection between the gut and the retina.
MeSH term(s)	Animals ; Mice ; Retinal Cone Photoreceptor Cells/metabolism ; beta Carotene/metabolism ; Vitamin A/metabolism ; Retina/metabolism ; Oxygenases/metabolism ; Membrane Proteins/metabolism
Chemical Substances	beta Carotene (01YAE03M7J) ; Vitamin A (11103-57-4) ; Oxygenases (EC 1.13.-) ; Stra6 protein, mouse ; Membrane Proteins
Language	English
Publishing date	2022-09-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddac242
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