Understanding the physiological role of retinol-binding protein in vitamin A metabolism using transgenic and knockout mouse models

doi:10.1016/S0098-2997(03)00038-4

Molecular Aspects of Medicine

Volume 24, Issue 6, December 2003, Pages 421-430

https://doi.org/10.1016/S0098-2997(03)00038-4 Get rights and content

Abstract

Retinoids (vitamin A and its derivatives) play an essential role in many biological functions. However mammals are incapable of de novo synthesis of vitamin A and must acquire it from the diet. In the intestine, dietary retinoids are incorporated in chylomicrons as retinyl esters, along with other dietary lipids. The majority of dietary retinoid is cleared by and stored within the liver. To meet vitamin A requirements of tissues, the liver secretes retinol (vitamin A alcohol) into the circulation bound to its sole specific carrier protein, retinol-binding protein (RBP). The single known function of this protein is to transport retinol from the hepatic stores to target tissues. Over the last few years, the generation of knockout and transgenic mouse models has significantly contributed to our understanding of RBP function in the metabolism of vitamin A. We discuss below the role of RBP in maintaining normal vision and a steady flux of retinol throughout the body in times of need.

Section snippets

Vitamin A metabolism and function

Vitamin A plays an essential role in maintaining mammalian health. It is required for many crucial biological functions such as vision, reproduction, growth and immunity (Goodman, 1984; Napoli, 1996). Since animals are incapable of vitamin A synthesis, all retinoids within the body (vitamin A and its metabolites) must be obtained from the diet as preformed vitamin A (retinyl esters, retinol and a very small amount of retinoic acid) from animal products or as provitamin A carotenoids from fruits

The role of RBP in vision

The visual cycle is driven by retinal derived from circulating retinol (Goodman, 1984; Wald, 1968). Within the retina, photoreceptor function depends on a specific vitamin A metabolite, 11-cis-retinal (Wald, 1968) which forms a Shiff’s base with photoreceptor opsin to generate the visual pigment rhodopsin. Photoisomerization of the chromophore from 11-cis to all-trans-retinal is the initial event of the visual cycle. This light-catalized isomerization induces a conformational change in opsin

References (59)

A.J. Adler et al.
Human interphotoreceptor matrix contains serum albumin and retinol-binding protein
Exp. Eye Res.
(2000)
A.R. Aldred et al.
The cerebral expression of plasma protein genes in different species
Comp. Biochem. Physiol. B. Biochem. Mol. Biol.
(1995)
H.K. Biesalski et al.
Biochemical but not clinical vitamin A deficiency results from mutations in the gene for retinol-binding protein
Am. J. Clin. Nutr.
(1999)
W.S. Blaner et al.
Spatial distribution of retinol-binding protein and retinyl palmitate hydrolase activity in normal and vitamin A-deficient rat liver
J. Nutr.
(1985)
B.V. Bui et al.
Retinal anatomy and function of the transthyretin null mouse
Exp. Eye Res.
(2001)
A.D. Cooper
Hepatic uptake of chylomicron remnants
J. Lipid Res.
(1997)
C. Eckhoff et al.
Human plasma all-trans, 13-cis and 10-cis-4-oxoretinoic acid profiles during subchronic vitamin A supplementation: comparison to retinol and retinyl plasma levels
J. Nutr.
(1991)
I.J. Goldberg
Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis
J. Lipid Res.
(1996)
D.S. Goodman et al.
Tissue distribution of newly absorbed vitamin A in the rat
J. Lipid Res.
(1965)
M.H. Green et al.
Variation of retinol utilization rate with vitamin A status in the rat
J. Nutr.
(1987)

K. Gregory-Evans et al.

Genetic blindness: current concepts in the pathogenesis of human outer retinal dystrophies

Trends Genet.

(1998)

P. Kastner et al.

Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life?

Cell

(1995)

D.J. Mangelsdorf et al.

The nuclear receptor superfamily: the second decade

Cell

(1995)

R.L. Martone et al.

Retinol-binding protein is synthesized in the mammalian eye

Biochem. Biophys. Res. Commun.

(1988)

J.L. Napoli

Biochemical pathways of retinoid transport, metabolism, and signal transduction

Clin. Immunol. Immunopathol.

(1996)

J.L. Napoli et al.

Biogenesis of retinoic acid from β-carotene

J. Biol. Chem.

(1988)

J.A. Olson

Provitamin A functions of carotenoids: the conversion of β-carotene into vitamin A

J. Nutr.

(1989)

L. Quadro et al.

Muscle expression of human retinol-binding protein (RBP). Suppression of the visual defect of RBP knockout mice

J. Biol. Chem.

(2002)

A. Ruiz et al.

Molecular and biochemical characterization of lecithin retinol acyltransferase

J. Biol. Chem.

(1999)

N. Wang et al.

Transport of 22:6n-3 in the plasma and uptake into retinal pigment epithelium and retina

Exp. Eye Res.

(1993)

R.H. Zetterstrom et al.

Localization of cellular retinoid-binding proteins suggests specific roles for retinoids in the adult central nervous system

Neuroscience

(1994)

R. Zolfaghari et al.

Lecithin: retinol acyltransferase from mouse and rat liver. cDNA cloning and liver-specific regulation by dietary vitamin A and retinoic acid

J. Lipid Res.

(2000)

A.B. Barua et al.

Chemical synthesis of all-trans-[11-3H]retinoyl beta-glucuronide and its metabolism in rats in vivo

Biochem. J.

(1989)

A.B. Barua et al.

Synthesis and metabolism of all-trans-[11-3H]retinyl beta-glucuronide in rats in vivo

Biochem. J.

(1988)

W.S. Blaner et al.

Retinol and retinoic acid metabolism

J.D. Chen et al.

A transcriptional co-repressor that interacts with nuclear hormone receptors

Nature

(1995)

S.R. Das et al.

Retinoid metabolism in cultured human retinal pigment epithelium

Biochem. J.

(1988)

V. Episkopou et al.

Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and thyroid hormone

Proc. Natl. Acad. Sci. USA

(1993)

M.T. Flood et al.

Human retinal pigment epithelium in vitro: organization, ultrastructure, and biochemistry

Birth Defects Orig. Artic. Ser.

(1982)

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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.
A high fat diet fosters elevated bisretinoids
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High dietary fat intake is associated with metabolic dysregulation, but little is known regarding the effects of a high fat diet (HFD) on photoreceptor cell functioning. We explored the intersection of an HFD and the visual cycle adducts that form in photoreceptor cells by nonenzymatic reactions. In black C57BL/6J mice and albino C57BL/6J^c2j mice raised on an HFD until age 3, 6, or 12 months, chromatographically quantified bisretinoids were increased relative to mice on a standard diet. In vivo measurement of fundus autofluorescence, the source of which is bisretinoid, also revealed a significant increase in the HFD mice. Additionally, mice provided with a diet high in fat presented with elevated retinol-binding protein 4, the protein responsible for transporting retinol in plasma. Vitamin A was elevated in plasma although not in ocular tissue. Bisretinoids form in photoreceptor cell outer segments by random reactions of retinaldehyde with phosphatidylethanolamine. We found that the latter phospholipid was significantly increased in mice fed an HFD versus mice on a control diet. In leptin-deficient ob/ob mice, a genetic model of obesity, plasma levels of retinol-binding protein 4 were higher but bisretinoids in retina were not elevated. Photoreceptor cell viability measured as outer nuclear layer thickness was reduced in the ob/ob mice relative to WT. The accelerated formation of bisretinoid we observed in diet-induced obese mice is related to the high fat intake and to increased delivery of vitamin A to the visual cycle.
Crosstalk between the liver and kidney in diabetic nephropathy
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Diabetic nephropathy (DN) is a serious complication of diabetes, and its pathogenesis has not been fully elucidated. Recently, communication between organs has gradually become a new focus in the study of diseases pathogenesis, and abnormal interorgan communication has been proven to be involved in the occurrence and progression of many diseases. As an important metabolic organ in the human body, the liver plays an important role in maintaining homeostasis in humans. The liver secretes a series of proteins called hepatokines that affect adjacent and distal organs through paracrine or endocrine signaling pathways. In this review, we summarize some of the hepatokines identified to date and describe their roles in DN to discuss the possibility that the liver-renal axis is potentially useful as a therapeutic target for DN. We summarize the important hepatokines identified thus far and discuss their relationship with DN. We propose for the first time that the “liver-renal axis” is a potential therapeutic target in individuals with DN.
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Transformation of white into brown fat (“browning”) reduces obesity in many preclinical models and holds great promise as a therapeutic concept in metabolic disease. Vitamin A metabolites (retinoids) have been linked to thermogenic programming of adipose tissue; however, the physiologic importance of systemic retinoid transport for adipose tissue browning and adaptive thermogenesis is unknown.
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We show that cold stimulation in mice and humans leads to an increase in circulating retinol and its plasma transporter, Rbp. In Rbp^−/- mice, thermogenic programming of adipocytes and oxidative mitochondrial function are dramatically impaired in subcutaneous white fat, which renders Rbp^−/- mice more cold-sensitive. In contrast, retinol stimulation in primary human adipocytes promotes thermogenic gene expression and mitochondrial respiration. In humans, cold-mediated retinol increase is associated with a shift in oxidative substrate metabolism suggestive of higher lipid utilisation.
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Understanding the physiological role of retinol-binding protein in vitamin A metabolism using transgenic and knockout mouse models

Abstract

Section snippets

Vitamin A metabolism and function

The role of RBP in vision

Exp. Eye Res.

Comp. Biochem. Physiol. B. Biochem. Mol. Biol.

Am. J. Clin. Nutr.

J. Nutr.

Exp. Eye Res.

J. Lipid Res.

J. Nutr.

J. Lipid Res.

J. Lipid Res.

J. Nutr.

Trends Genet.

Cell

Cell

Biochem. Biophys. Res. Commun.

Clin. Immunol. Immunopathol.

J. Biol. Chem.

J. Nutr.

J. Biol. Chem.

J. Biol. Chem.

Exp. Eye Res.

Neuroscience

J. Lipid Res.

Chemical synthesis of all-trans-[11-3H]retinoyl beta-glucuronide and its metabolism in rats in vivo

Biochem. J.

Synthesis and metabolism of all-trans-[11-3H]retinyl beta-glucuronide in rats in vivo

Biochem. J.

Retinol and retinoic acid metabolism

A transcriptional co-repressor that interacts with nuclear hormone receptors

Nature

Retinoid metabolism in cultured human retinal pigment epithelium

Biochem. J.

Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and thyroid hormone

Proc. Natl. Acad. Sci. USA

Human retinal pigment epithelium in vitro: organization, ultrastructure, and biochemistry

Birth Defects Orig. Artic. Ser.