McCollum Award transport, cellular and storage14 Kaare

R Norwn

and

ABSTRACT metabolism.

Dietary

enterocytes.

poration

Vitamin

A absorption,

Blomhoff vitamin

A with

emphasis

cellular

uptake,

storage,

and

retinyl

esters

its

to retinol

in

by enterocytes. Carotconverted to retinol in

retinol

chylomicrons

on

intracellular

are hydrolyzed

before absorption and then partially

In enterocytes

into

1 992:

discuss

transport,

the intestinal lumen enoids are absorbed the

Rune

We

absorption,

Lecture, uptake,

is esterified

together

with

before

optimal vitamin

amounts A intake.

ofretinol despite Furthermore,

Chy-

lomicrons reach the general circulation by way ofthe intestinal lymph, and chylomicron remnants are formed in the blood cap-

gene expression acid-responsive

illaries. retinol,

thereby mediates the expression. Modification

The remnants, which contain almost are cleared by the liver parenchymal also by cells The uptake

extent spleen.

in blood, is most

ceptors for low-density receptor-related protein. esters

rapidly

are

binding

to retinol,

Normally,

most

Nutr

retinol

retinoic excert

acid

KEY

WORDS

leukemia, receptor,

Acyl

on retinol-binding as retinyl esters

acyltransferase

acyltransferase

to the possible on cell

sequences of target

of

(retinoic genes, and

vitamin A in gene by covalently bound

mechanisms

whereby

retinoids

functions.

in

The

cellular

term

exhibit noids

the biological includes the

many

synthetic

uptake,

vitamin

storage,

and

intracellular

A is used for all compounds

that

activity of retinol, whereas the term retinatural forms of vitamin A as well as the

analogs

transport

of retinol. and

storage

1 gives

Figure in the

an

overview

body.

(ARAT),

(LRAT),

retinoids, retinol, retinol-binding retinyl ester, stellate cells, vitamin

to short DNA in the vicinity

ultimate actions of key proteins

transport,

metabolism.

coming

1992:56:735-44.

CoA:retinol

lecithin:retinol

adds actions

of retinoid chylomicron,

by binding elements)

their

absorption,

to retinol-

binds

absorbed

cell is transferred which store retinol

.1in J (‘liii

droplets.

which

ofthe

in daily retinoid-

fluctuations of cellular

Several reviews of vitamin A metabolism have been published recently (3-7). Here we discuss vitamin A with emphasis on its

lipoproteins or a low-density lipoproteinIn the liver parenchymal cells the retinyl

into the liver parenchymal protein to stellate cells, lipid

all the absorbed cells, and to some

bone marrow, adipose tissue, and probably mediated via surface re-

hydrolyzed

protein.

normal a group

a major role its production tissues with

binding proteins and enzymes regulate intracellular metabolism and transport. The family ofnuclear retinoid receptors regulates

incor-

triacylglycerols.

plasma and at the cellular level. The liver plays with its processing and storage of retinol, and with of retinol-binding protein (RBP), which provides

protein A

myeloid (RBP),

Absorption

RBP

The

of vitamin main

dietary

A

sources

of vitamin

A are provitamin

A ca-

rotenoids from vegetables and preformed retinyl esters from animal sources. Little quantitative data are available on the effiIntroduction It is unlikely

that

scope of research “Fat-Soluble A” In view reproduction

McCollum

and

that would in 1915.

from

that

(2) starts

derived

through

the of

retinol. mans,

“Our but

several

fat.

since the identification of and mechanism of action research topics for many

the first chapter

book J”iiamin .4 as follows: vitamin A, which is extensive been

imagine postulation

vitamin A plays in vision, cell growth, differentiation,

and cancer, it is not surprising that vitamin A, its chemistry, metabolism, have been stimulating and important Moore

their

present still far

distinct

in his classical

1957

information from complete,

about has

channels,

which

have

absorption of provitamin and cryptoxanthin) and

Carotene

that

efficiency

twelfth verted

that,

(on the basis of other to retinol

between

depends

It is assumed

one-sixth

is by passive

absorption

it appears

sorption

of the essential roles and morphogenesis,

scientists. Thomas

( 1) could

Davis

result

ciency of intestinal [3-, and -‘y-carotene

in

5% and

diffusion

50%

on an adequate humans

ofweight)

consuming ofdietary

provitamin carotenoids, in the enterocytes (5).

A carotenoids their conversion and,

(a-, to in hu-

is absorbed

(5).

quantity

of dietary

a “normal” fl-carotene,

is absorbed In humans

Abdiet,

and

one-

and conand some

) From the Institute for Nutrition Research. Faculty of Medicine. University ofOslo, Norway. 2 Presented at the I 992 American Society for Clinical Nutrition Annual

May 1. Baltimore. Supported in part by a grant from the Norwegian Research Council for Science and the Humanities. the Norwegian Cancer Society. and the Anders Jahres Foundation. KR Norum was a Fogarty Scholar-in-Residence at the National Institutes of Health during preparation ofthe article. 4 Address reprint requests to KR Norum. P0 BOX 1046. Blindern, 03 16 Oslo, Norway. Meeting, 3

merged stream

their contributions at various of advancing knowledge.” This

Because

ofthe

in physiological in

Im

excess,

the

J (‘lipi Nuir

pivotal

role

ofretinoids

concentrations, body

must

1992:56:735-44.

and regulate Printed

points into the general statement is still true. when

their their

they

toxicity

concentrations

in USA.

are present

when

they

are

both

© 1992 American

Downloaded from https://academic.oup.com/ajcn/article-abstract/56/4/735/4715594 by Washington University, Law School Library user on 11 April 2018

in Society

for Clinical

Nutrition

735

736

NORUM

AND

BLOMHOFF

ROH = retlnol RE = retlnyl ester CM = chylomicron CMR = chylomlcron remnant RBP = retlnol binding proteIn TTR = transthyretln RA =retlnolcacld RAR = retlnoic acId receptor RXR = 9-cls retlnolc acId receptor TG = triacylglycerol VLDL = very low densIty Iipoproteln

CM-RE

I

-carotene RE ROH

Intestinal

lumen

FIG 1. Major pathways for retinoid transport in the body. REs are hydrolyzed to ROH before absorption. Carotenoids are partially converted to ROH in the enterocytes, where ROH is esterified and incorporated into CMs together with TGs. CM reach the general circulation via the intestinal lymph. CMRs contain almost all the absorbed retinol, and are cleared mainly by the liver parenchymal cells. In the liver parenchymal cells, REs are hydrolyzed to ROH, which binds to RBP. Most of the ROH in the liver parenchymal cell is transferred to stellate cells, which store REs in lipid droplets. Most ofthe RBP-ROH secreted from liver is complexed with TTRs in plasma. The RBP-ROH is presumably taken up by cell surface receptors. In cells some ROH is metabolized to all-trans RA, and other retinoic acid isomers and derivatives (9-cis RA and 3,4 didehydro retinoic acid), which are ligands for nuclear receptors like RARs or RXRs.

other

species,

intact

and

a significant transported

fraction from

the

of carotenoids gut

via the

is absorbed

intestinal

effects oftetrahydrolipstatin, sorption of retinol and

lymph.

Maiani et al (8) presented data suggesting that the rate of 9carotene absorption and its conversion to retinol may be enhanced in elderly individuals. Their data, however, could also be explained

by the

recent

findings

of Krasinsky

et al (9),

who

bile

duct-fistulated absorption that the retinyl lipase ofpancreatic ( 19) reported

Ong

version

by facilitated

(10-

offl-carotene

and

both

Huang

(1 5), and nals

(10)

(1 3), Goodman

et al (14),

by two

peripherally

by peripheral

suggests that II [CRBP(II)] somal

retinal may

carotene

and

may

may

by Goodman

Olson

and

Hayaishi

subsequently

generated

reduced to retinol by a reductase. that this was accomplished by a

recent

work

by

Kakkad

and

bound to the intestinal cellular be reduced by a membrane-bound

Ong RBP

esters

from

absorption

into

the diet

are hydrolyzed

the enterocytes.

assumed to be responsible with pancreatic insufficiency A given as retinyl palmitate, with Tween ( 17). Fernandez

Pancreatic

in the lipase

(16)

type micro-

intestines has been

for the hydrolysis, because patients have reduced absorption of vitamin but not as free and Borgstrom

tions, retinol

retinol emulsified (1 8) studied the

Downloaded from https://academic.oup.com/ajcn/article-abstract/56/4/735/4715594 by Washington University, Law School Library user on 11 April 2018

from

quality

of fat what

studies

whereas,

et al (9, 20)

is apparently

diet

(5).

More retinol

discussed,

have

palmitate

system

do not know

whether

as retinyl

esters

retinyl

Ong

esterified a major

(25)

acyltransferase found

that

by LRAT (25), role in the normal

research

is needed This

is, as

important

for

as a label

enterocytes

retinol

leaves (Fig

preferentially distributed

complexed

and that CRBP(II) carrier-mediated

(25,

26).

via the 1). We with between

for the esterification acyltransferase (ARAT) (LRAT)

to

for studying

in chylomicrons

or are randomly produced.

Two enzymes are important in enterocytes: acyl CoA:retinol and

absorbed

absorption.

esters are carried

large or small chylomicrons, all sizes of the chylomicrons

and lecithin:retinol

are

concentra-

especially

is used

chylomicron metabolism (20-22). Most of the retinol absorbed into lymphatics

esters

of enterocytes.

at pharmacological

influence

retinyl

retinyl

borders

by passive diffusion. Absorption of and it depends on both the quantity

in the

factors

in which

the long-chain the brush

concentrations

diffusion,

it can be absorbed is probably < 75%,

Krasinski by

in rats

in physiological

determine

be further

Retinal

that

by an enzyme

Retinol

and

The apo-caroti-

enzyme.

Retinyl before

( 1 5),

that

enzymes.

or to retinol.

central cleavage is presumably In contrast to earlier reports enzyme

of controversy

reported

separate

cleavage acid

a subject

indicates

as originally

to retinoic

cytosolic

been

centrally,

formed

processed

have

by Dmitrovskii

1 3). Work

be cleaved

to retinol

hydrolyzed

aband

rats. They found that tetrahydrolipstatin inof retinyl palmitate but not retinol, suggesting palmitate was hydrolyzed by a carboxyl ester origin. Most recently, however, Rigtrup and

hibited

found that older subjects had increased postprandial retinyl ester concentrations due to delayed plasma clearance of chylomicrons. The enzymatic mechanisms responsible for intestinal con-

a lipase inhibitor, on intestinal palmitate in thoracic duct-

retinyl

of retinol (23, 24)

MacDonald

to CRBP(II)

was

may therefore play absorption of retinol.

VITAMIN

uncomplexed It has been

In contrast, by ARAT. during terifies

retinol suggested

in membranes that LRAT

absorption of a normal excess retinol when large

becomes

(5). Note,

saturated

found

that

in the human

type)

LRAT

load doses

that

was the physiologically

esterification even at high physiological With pharmacological doses Rasmussen retinyl

palmitate

fold,

activity

of a large

Randolph nor

and

LRAT

dose

(30)

recently

decreased

vitamin

A, and

iological

needs

intestinal

in the

state

that

A-deficient

ready

for

CRBP(II) transcription via the nuclear retinoid of retinol retinoic CRBP(II),

CRBP(II)

normal

(Figure

0

2).

ARAT

depleted

of phys-

to maintain of

vitamin

(RXRE)

A

was de-

suggesting

regulated

.

by

We speculate

retinoic

that

acid

high

doses

in enterocytes.

Uptake

of chylomicron

retinyl

esters

in peripheral

7

5

HOURS AFTER RETINOL INTAKE

that

in the diet may lead to an increased concentration of acid in enterocytes and an increased expression of and thus be partly responsible for regulation of retinol

esterification

C

medication delayed ab-

neither

(3 1 ).

is positively

receptors.

several

below

animal

element

promotor

cell

the presumed

whenever it may become available.” Recently, a retinoic acid responsive the

(27)

ARAT

of rats

with

assimilation

in

the

well for

tected

at

intestines

“fits

14

of retinol. found that

palmitate that

pM

PLASMA,

for retinol

Furthermore, in vitro (29),

reported

small

this

decrease

of retinyl

of the vitamin

LRAT

not

rats. ARAT

oral

Ross

enzyme

ofintestinal

did

amounts in vitamin A-deficient with etretinate, which inhibits sorption

and Ong

concentrations et al (28)

the activity

increased the ARAT

whereas

Quick

important

RETINYL ESTERIN

and ARAT esand CRBP(II)

cell line (an enterocyte-like

Caco-2

737

TRANSPORT

may be esterified esterifies retinol

of retinol, are absorbed

however,

A

FIG 2. A normal adult male ingested 45 mg ( 150 tmol) retinol as retinyl palmitate. three times, 4 wk apart. Two experiments were done before (open symbols). and one after (closed symbols) three daily doses of SO mg etretinate. The last dose of etretinate was given together with retinyl palmitate. Retinyl palmitate was dissolved in 50 mL arachidis oil and given together with a light breakfast. The person did not eat the next 8 h, when hourly blood samples were taken. Retinyl esters were measured by standard methods (23).

tissues Most the

retinyl

particles

in the

esters when

liver,

in the

blood

are converted circulation

chylomicron

remnants

peripheral

Although

present

they

extrahepatic

uptake

delivery of fatty acids, tissue, skeletal muscle,

35)

found

content

after

a large

are

oral

may

SO Lie,

unpublished

observations

agree

with

the data

showed that retinol disappeared ofthe marmoset. Chylomicrons complex for delivering tissues with intensive

be important

in the

carotenoids marrow

to adipose (32, 33). Re-

and marmoset monkeys dogs were also important.

of retinyl

did not store doses ofretinol

Norum,

by the

in man

bone marrow, however, long-term intake ofhigh and KR

cleared

reported that, although liver was retinyl ester removal in all species

marrow

dose

mainly

and bone

in rabbits pigs, and

bone

that

with

remnants

(5).

ofremnants

examined, the bone marrow and the spleen in rats. guinea We recently

to chylomicron

sterols, retinol, kidney, and

cently. Hussain et al (34, the main site ofchylomicron

remain

chylomicrons

increases

palmitate.

The

human

retinyl esters even after (B Skrede, R Blomhoff, observations,

from

in retinol

Hussain

1992).

These

et al (35),

which

rapidly from the bone marrow may be an important transport

cholesterol, cell proliferation

retinol, and

and carotenoids differentiation

to such

as bone marrow and spleen. We have shown that human myeloid leukemia cells take up retinyl esters from chylomicron remnants in vitro, decreased in vivo;

and

that

this

uptake

cell proliferation Tsutani et al (38)

leads

to both

differentiation

(36, 37). This uptake also takes place showed a reduction of leukemia cell

growth in a patient with acute promyelocytic leukemia with retinyl palmitate. Furthermore, we recently showed that

peripheral

white

blood

and

cells

from

both

normal

treated in vivo

individuals

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and patients

homozygous

crease

their

mitate

(39).

Uptake

retinol

after

remnants

appears

ofDisse,

mediated

uptake

lipolytic

involved

in uptake is being

esters

bind

(40).

via a process

sequestration

processes,

and

receptor

chylomicron

The

pal-

by liver

then

cells (hepatocytes)

(LDL) can

in-

of retinyl

up by the liver

into parenchymal

the low-density-lipoprotein protein

doses

chylomicron-remnant

further

tor-related

oral

retinyl

are taken

to involve

the space

ceptors

hypercholesterolemia,

large

of chylomicron-remnant

Chylomicron that

for familial

content

and

(40). Both

the

remnants

quantitative

role

in

receptor-

LDL

recep-

and

may

be

of these

two

re-

debated.

Once chylomicron-remnant

retinyl

esters

have

been

taken

up

by liver parenchymal cells, a rapid hydrolysis takes place, most probably catalyzed by a plasma membrane retinyl ester hydrolase (41). Subeellular fractionation (42) and autoradiographic studies (43) suggest that chylomicron vitamin A is rapidly transferred to the endoplasmic vesicular transport Retinol and for

binds

to RBP,

RBP-retinol secretion

reticulum. Whether this transfer occurs via or via CRBP in the cytosol is not known.

presumably

is then (44).

This

in the endoplasmic

transferred secretion

secretion

Vitamin

A repletion

of RBP-retinol

from

Golgi

is influenced

status: in overt vitamin A-deficient such that plasma concentrations creased.

to the animals, of RBP

leads the

(44).

by

vitamin

A

secretion is reduced and retinol are de-

to an immediate liver

reticulum, compartment

increase

in

NORUM

738 Note

that

the

cytes

is different:

with

long-chain

together

handling

with

do not

by enterocytes

(TG)

incorporate

in the core

retinyl

of very-low-density

retinyl

ester

lipoproteins

A may

hepatocytes

be crucial

accumulation

retinol packed

lished observations, with antisense cDNA

199 1) found for CRBP(I)

(VLDLs).

or retinoic

The

in handling

for the regulation

TG

terify retinol. Addition ofretinol

This

was

in induction

ofthe

et al using

difference

between

doses

of vitamin

normal storage

ofretinol

rapidly secreted out of hepatocytes (47). However, several explanations are possible and deserve further investigation

the

mechanism

may give us better metabolism and

ofthese matters of normal retinol the toxicity

behind

other be-

of retinol

acid

feedback

A-depleted

Interestingly, rise

retinoic

cells

of retinol for

In vitamin retinyl

from

storage

parenchymal

in the

taken

ofthe

most

up by hepatocytes

chylomicron-remnant is rapidly

to RBP (44). The uptake of retinol rapid to be accounted for by secretion the general

circulation

thermore,

during

ously given chylomicrons we observed that retinol stellate cells, the transfer, Normally, liver (20). (52-54);

the

of the

stellate

esters,

whereas

total retinol Redgrave years

ago

amounts

rest

vitamin

in the

esters

Chemical analysis cells revealed that is retinyl esters, Triacylglycerols mass, and

cells

blocked (51).

is present liver total

(59,

in the retinol

of retinyl

fraction

of the

60) showed

the ability The

several

to store

large

size and number

A status

ofthe

on the vitamin between 35%

not seem

to be related

A status ofthe animal. and 50% of the lipid to dietary

fat or vitamin

A(6). A small,

acute

load

of retinol

does

not

stellate cells of vitamin A-depleted rats may be related to the amount ofCRBP(I) cells. Rats ofCRBP(I) CRBP(II). LRAT cells

fed normal in stellate

amounts cells

donor

(6 1 , 62),

reduced

concentrations

of vitamin

A-deficient

rats

CRBP(I),

of retinol

effective

may

in liver

A have large amounts

Because

is an

accumulate

(32). This observation and/or LRAT in these

ofvitamin

(47).

like

intestinal

for esterification of CRBP(I)

account

may

represent

in regulating in stellate

be explained

a pos-

cellular

uptake

cells of vitamin

by reduced

LRAT

was

more

potent

which

(most

than

increased

likely

the

was

retinol

10 times

stellate

for

more

cells)

than

in

in pa-

for

the

be secreted

may

directly

from

to the

liver

from

general

cells

its main

storage

circulation,

ferred from stellate cells to hepatocytes. Although there is some disagreement how much RBP stellate cells contain and RBP,

these

cells

for exporting onstrated Yamada stellate in

apparently the

with

(53,

67,

the RBP 68).

We

cells.

We also

found

that

medium

route

of mobilization apo RBP can

that

cell retinol,

stellate

when

they

that

(69)

be trans-

is necessary

recently

dem-

for RBP, whereas mRNA for RBP in

stellate

secreted

in stellate

first

literature about they synthesize

in the whether

that stellate cells contain mRNA et al (70) were unable to detect

a serum-free

native

do contain

vitamin

locus

or it may

cells

were

RBP-retinol.

cultured An

alter-

may also take place. Recent data bind to stellate cells, make a complex

and

then

be released

into

the circulation

as RBP-retinol (69) (Fig 1). The ability ofliver cells to control the storage and mobilization of retinol ensures that the blood plasma retinol concentration to 2 jzmol/L

is close

A intake. CRBP(I) RBP

despite

It is likely and LRAT,

by retinol,

by liver

normal

fluctuations

control

uptake,

retinol

vitamin

in daily

that the retinoid-regulated in addition to saturation

of and

expression ofCRBP(I)

storage,

and mobilization

cells.

animal.

lipid droplets from rat liver stellate I 2% and 65% of the total lipid mass

depending comprise

receptors

and Ross (30) most recently found LRAT declined as rats became vitamin rapidly after oral repletion with retinol.

of retinol

Retinol cells

suggest

percent

form

a larger

on the vitamin

of these between

this does

have

RBP carrier

Ninety-eight

droplets.

in lipid

depends

droplets

cells

Fur-

rats previ-

retinyl esters, hepatocytes to

in the

(55-57). (58) and Wake

stellate

ofretinyl

ofthese

parenchymal

is unesterified and Vakakis liver

cells.

A is present

cells.

from

against retinol

retinoids of the

is in parenchymal

cell

that

total 90%

in the liver mediating

of stellate

of livers

ofantibodies RBP was the

ofthe body’s cells contain

h)

stellate cells is too the hepatocytes to

labeled with radioactive was transferred from

and the addition suggesting that

most Stellate

in the from

perfusion

2-4

can take up the RBPsecrete retinol bound

by uptake

followed

an in situ

(within

stellate cells for a carrier

the transfer is RBP, because stellate cells retinol complex (49, 50) and hepatocytes

results showed

(66).

Mobilization

rats,

as retinol to perisinusoidal (Fig 1). A plausible candidate

transferred (32, 48)

cells

recently

to stellate

liver

A-sufficient

esters

cells

also

activity, cells

(unpub-

cell types

et al (65)

storage. ofretinol

acid

LRAT

in

acid

may

A Nilsson

element is present in the CRBP(I) ofCRBP(l) gene transcription

important

retinyl ester accumulation

nonparenchymal

overload.

retinoic

animals

renchymal Transfer

and

activity. Thus, Randolph that the activity ofhepatic A deficient and recovered the

we and

that stellate cells transfected have a reduced ability to esacid to different

control

mechanism

of retinol and The reduced

Thus,

(63, 64). Smith

that a retinoic acid-responsive promotor, suggesting that itive

and

esters.

ofCRBP(I)

by retinoic

the delivery of retinol to tissues. The differences between hepatocytes and enterocytes may be explained by the very high production of RBP in hepatocytes, thus unesterified retinol is

cause a better understanding insight into the regulation

ofretinyl

with

(45), and Thompson laid the ground for

as a tag for chylmicrons. and

together

BLOMHOFF

hepato-

of chylomicrons;

esters

first observed by Ross and Zilversmit (46), an important observation that enterocytes

and

rapidly esterify the absorbed and secrete the retinyl esters

triacylglycerols

hepatocytes in the core

of retinol

enterocytes fatty acids

AND

by

Turnover Vahlquist

recycling

of plasma

(7 1) suggested

20 y ago

in rats

(72-76).

retinol retinol

that leaves the plasma is recycled turnover rate is more than an order

of plasma liver,

reduced

RBP

In fact,

the utilization

molecule utilization. In rats, and

rate

recycles Green

for retinol

blood.

it is now

(72-75).

Green

and

turnover

remaining recycling

retinol

This

was

in rats,

the

75),

30%

is to other

tissues.

from

the kidneys

and other

of

plasma greater

an average before

(72.

by

majority

retinol

irreversible

et al estimated

is to kidneys

up verified

because the ofmagnitude

7- 13 times Lewis

taken

recently

that

thought

Thus,

to the plasma and

retinol the

to the

that

may

than

be recycled

retinol

tissues

in stellate

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and

that

50%

20% The

source

extrahepatic

is to of

VITAMIN tissues is not extrahepatic RBP

(76,

tissue

yet known. It is interesting in this regard tissues, including the kidneys, contain

77).

Notably,

contains

Makover

relatively

et al (76)

high

that many mRNA for

reported

concentrations

A TRANSPORT

that

adipose

of RBP

retinol

bound

recycling

to RBP

(78).

These

important

tissue may contribute and pools of RBP, and

observations

substantially to the have an important

the uptake LDL

These

of retinol

bodies.

body’s role in

cells

RBP but

to retinol-binding

unbound

retinol

would

is in equilibrium

be available

nism

without

involvement

basis may

of some be some

findings, nonspecific

mechanism

Retinal

pigment

Heller

Bok

retinal

pigment

by a 600-fold retinal cells binding

cells

this

A saturable

On

epithelial

other likely

in an

autoradiographic

(RPE)

to the

cells.

RBP

to isolated

surface

binding

RPE

of

was inhibited

cells.

to other saturable

the cell-associated concluded that et al (84)

Ottonello binding

molecular might

‘251-labeled RBP was not showed

to RPE weight

16000

be CRBP(I).

and

Their

RBP-retinol internalized

that

became

cells

retinol

The

binding

data

suggested

that

indicate

that

the uptake of retinol and observed a fourfold reduction

incorporated

when

retinyl

ester

released with

exists between because they

formation

maximum

receptor

binding

and

Hepatocytes (49,

from 50).

to the receptor constant was

liter and

the

plasma

A selective

stellate stellate

of 63

of

protein link

can

of RBP

stellate cells was observed in a study RBP and other ligands were injected

expect

inhibited.

take

pH.

up

by liver

barrier

stellate after

Early

Sertoli

cells

is dependent express

CRBP(I)

RBP

of[3H]retinol-RBP

via an RBP receptor, data also suggest that and

ma-

surrounding

spermatogenesis

uptake

complexes The as-

The

membrane

the

basolateral

cells.

Interestingly,

were

also

found

in these

RBP

receptor-mediated

on

receptors.

was

reported

RBP was not taken cells take up retinol

but retinol

is further

that RBP is not taken up by the

processed

of retinol

by CRBP(I).

Placental

brush

to retinyl

the

both

retinol

parenchymal

and in vivo and

by Senoo et al (86). lodinated intravenously into rats and

Downloaded from https://academic.oup.com/ajcn/article-abstract/56/4/735/4715594 by Washington University, Law School Library user on 11 April 2018

of retinol and

specific

receptor

further

for the developing Sivaprasadarao

is an

that

con-

processing

for RBP.

Scatchard

fetus, and

analysis

higher-affinity

retinol

might

(90,

brush presence

ofthe

both high components. form

and

Findlay

placental with the

the lower-affinity state after RBP bound and inol, or that apoRBP may have a lower affinity

91)

border of a

equilibrium

(3 nmol/L) and The authors be converted

to

transferred its retthan RBP-retinol

receptor.

Metabolism Until binding glected.

of retinol a few years ago the role of the many cellular retinoidproteins in intracellular retinol metabolism was neData now being presented, mainly from MacDonald

Ong

zymes.

there

cells

membranes

placenta.

the

that

by the

apparent

binding of ‘25I-labeled RBP revealed low (90 nmol/L) affinity-binding that

of CRBP(I)

suggest

studied binding of RBP-retinol to human membranes. The data are compatible

and

complex

data

who inwas

the choroidal

inside

The

barrier

border

and

concentrations

cells.

A is necessary

to cross

surface high

uptake

the blood-brain

for the

characterized Radiolabeled

000 (85).

transport

and cells.

barriers

that

specific

along

speculated A

cells cells

parenchymal

into anti-

on the surface ofliver parenchymal later it was also located in vesicles

(25),

Ong et al (26,

6 1), Quick

and Ross (30), Yost et al (62), indicate that the binding proteins

RBP-retinol uptake

RBP

a functional

was

at neutral

weight

liver

or endothelial

up the blood-testis

with

RBP cells.

(86).

epithelial

Vitamin

was fast, saturable, and specific. in the range of 30-70 nmol/L,

occurred

had a molecular

fIc’patoci’tc

RBP

the

was cross-linked with RPE membranes, and analyzed by electrophoresis and autoradiography.

sociation ofRBP The dissociation and

from a protein

retinol esterification, in total vitamin

B#{227}vik et al (85) recently identified and partially a membrane receptor in bovine RPE cells (85). RBP were

(88).

has

within 3 mm, by these cells.

associated

they

combines

esters

stitute

of ‘251-labeled RBP was complete in 1 mm, and the amount of cell-associated radioactivity was sevenfold higher at 22 than at 0 #{176}C. Because he found that unlabeled RBP-retinol could displace Heller

cells

whereas and stellate

immunocytochemical

by Shingleton et al (87). Because iodinated up by the cells, they concluded that Sertoli

localized

study

choroidal

The

and

asialooro-

Related results were reported by MacDonald et al (89), used autoradiography to study the uptake of intravenously jected ‘25I-labeled RBP by rat brain (89). 125I-labeled RBP

retinol.

only

by

Because

from RBP-retinol internalized. The

observations to be the pri-

excess of unlabeled RBP. Binding observed. Heller (83) also found

of ‘251-labeled

the

that there RBP-retinol

obtain

reported bound

molar was not

many is not

cells make

from

Acetyl-

and

was injected intravenously of liver with gold-labeled

cells

blood-brain

one would

receptors.

up

cells

in hepatocytes, parenchymal

results

taken

and

retinol,

retinol

with

cytoplasm

from RBP amount of

cells

(82) RBP

RBP

1 ). However, partitioning

by which

‘25I-labeled

after

in the

cells was determined.

in endothelial

injection, RBP was localized and stellate cells, whereas

spermatocytes.

mecha-

ofliver

mainly in both

by Kupffer

turing

by a nonspecific

of specific

epiz/ielial

and

RBP-retinol,

uptake

it is reasonable to conclude transfer of retinol from

to cell membranes (79-8 indicate that nonspecific mary

with

for cellular

was

Blood-testis

by which retinol is transferred fully understood. Because a small

agree

not

Sertoli

The mechanisms into cells are not

that

bound

types primarily

recovered recovery

data

deeper uptake

recovered

studies in which human RBP rats and traced in cryosections

suggest

of retinol.

Cellular protein

by different

was

somucoid was had appreciable

mRNA.

Most recently it was reported from Blaner’s laboratory that adipose tissue in rats contains a considerable amount of the body vitamin A store, and that adipose cells may produce and secrete that adipose production

739

That

are added

is, when

retinoids

to cell homogenates,

and

Ong

and Matsuura direct retinoids complexed the

with

retinoids

(27),

Randolph

and Ross (66), to specific enbinding

proteins

are metabolized

by

different organic

enzymes than if they are added solvent. Four main processes are

when dissolved in an involved in the intra-

cellular

metabolism

may

of retinol:

I) retinol

be esterified

and

NORUM

740 stored,

2) retinol

as retinoic bonds

with

cell

Esteri/icalion

be converted

proteins,

and

to a form

that

will

(or

is excreted

compound

partition

retinol

transported concentration

can

into

such

form

covalent

retinoic

from

with

acid)

may

the body.

If present

membrane

structure.

through an aqueous environment, in membranes, retinol is normally

retinol. esterify

Two retinol

spectively,

whereas

the

esterifying LRAT

other

retinol

two,

under

when

large

found

has been

activity is low when the enzyme activity

retinol LRAT

activity

liver

to be

the

stellate

in liver

cells

and

but

enter

stellate

cells

RPE

droplets. main intestinal

conditions,

ofretinol

ARAT

the intestinal

(92),

activity retinol

conversion

in the

cells

RPE

in intestine by LRAT

ofall-trans

It will

LRAT in ocular cells Retinol is esterified ported as retinyl (95) showed that tivity

and

and and

is

1000

and liver (93). The in RPE cells is linked

retinyl

esters

played Menton

a similar constant

liver.

Thus

cation

be important

is identical in lactating

retinol

to 1 l-cis

relative maximal (Km)

to the

liver.

mammary

cells. and

trans-

Randolph et al low LRAT acARAT

dis-

but a lower Michaelisgland compared with

concentrations gland

whether

in other gland

In contrast,

velocity (Vmax) in the mammary

at physiological

in the

to determine

to LRAT mammary

esters in milk-lipid droplets. the mammary gland contains

CRBP(I)

of retinol,

appears

to occur

esterifi-

It

of retinal

is generally

to opsin to nuclear in vision

however, activates also are retinoid

and

all-trans

1 l-cis retinoic

retinal covalently acid noncovalently

bound bound

retinoic acid receptors (RARs) and in transcription regulation,

are the active respectively.

retinoids Recently,

it was demonstrated

retinoic

binds

the three

nuclear

ligand-dependent isomerization

Furthermore,

retinoid

9-cis

X receptors

acid

(RXRs),

all effects many

been

to clarify

retinoic

which

factors (96, 97). Thus, not only in vision but that

of retinol in growth cells to l4-hydroxy-4,

retinoic

acid

cannot

regulation. Retinol is 14-retro-retinol, and

this compound was suggested to be the mediator (98). Many other retinoids, such as 13-cis retinoic

ofthese acid,

acid

a further

retinoic drogenase

(102).

to retinal

feedback

acid

loop

synthesis

Although

several acid

types

in vitro,

important.

Because

be synthesized negative

strain oxidation

in delivering

similar

to that

Posch

retinol-CRBP(I) thermore,

neither

formation

from

dizing volved

data

target

cells,

for retinol

rather nor

that

may

and

(103,

104).

to cellular

P-450

serum

ofcell

proteins

and

retinal

ethanol were

oxinot

other

and

lungs

acid

in

in-

with

this

(106). retinoid

species

that

accumulating carotenoids dosing increased retinoic is consistent

Fur-

also be synthesized

kidneys,

of retinoic

in humans

in rabbit

inhibited that

may

by

retinol.

isozymes

acid

In fact,

is supported

suggesting

liver,

directly

in a manner

esterification.

ketoconazole

retinoic

binding

are

by unbound

be a source

particularly

Retinoi’lation

retinol

synthesis

than

could

that

is bound

retinal

acid

enzymes

enzyme,

capable of absorbing and The finding that a-carotene centrations

suggested

to the proper

that

to

dehydrogenase-

retinol

in the intestine,

/3-carotene

retinoic

proteins

above

retinol

physiologically

binding

ethanol

indicate

Thus,

that

retinol-CRBP(I),

/3-carotene

convert

by different

enzymes and cytochrome in retinoic acid biogenesis.

Other

concentrations

these

directly

(102). for ret-

loop

all are

an alcohol

retinol

suggest

It

synthesis

be that

discussed

et al (105)

that

synthesis.

constitutes

large

that

it was

intracellular

involved

acid

because

from

cytosol

it might

acid

of dehydrogenases

are mediated

most

dehy-

acid-responsive

to cells.

of deermouse,

and

Recently,

alcohol

regulatory

it was demonstrated

proteins

acid.

ofADH3

retinoic

it is unlikely

by using

ethanol

In vivo,

toxic

including

dehydrogenases,

as an indication

a positive

be unlikely,

very

are

to assume

steps,

human

activation

such

in vi-

is synthesized

distinct

in retinoic

regulating

may

acid

of retinoic retinoic

acid

however,

acid

taken

du-

work

metabolites

via a retinoic was

and

more

a tendency

the

role

retinoic

Much

to retinoic

directly

observation

that

digit

by alcohol

to regulate

a regulatory

Physiologically.

by two

of retinal

shown

play

was suggested

inoic

of retinol

This

may

a positive

occurs

for ADH3

gene

element

synthesis

was

acid

retinoic has been

3,4-dide-

Retinoic

of these

whereby

oxidation

acid

role

There

and

3,4-

in evoking

( 100).

bud

possible

understood.

dehydrogenation and

wing

in

bud,

of the endoge-

101).

are equipotent

pathway

in situ is poorly

Takahashi bond

effects the reti-

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is small, subunits

tokeratins findings may

as ligands.

(1 10), suggest

reported

evidence

are retinoylated

in vitro

Breitman

(108)

cell lines

in a dose-dependent

latory

acid

and

in several

proteins proteins

suggested

the

wing

are

in tissues. acid conidea

(107).

and

regulation. it has

by

that

transcription may be important

also in transcription substitute metabolized

that

assumed

proteins

is needed

tamin A function. The metabolic

Interestingly,

proportion

(100,

present

retinoic

or as inter-

esters,

a large

acid

in the developing

from

predominantly

by ARAT. Activation

chick

3,4-didehydro-retinyl

retinoids

ADH3

the enzyme

A stores in liver are depleted, rapidly after retinol repletion

mg protein)

(per

process.

(99).

developing

comprise

and

function

catabolism

in the

plication

that

retinol,

retinoid

and

normally

Thus,

4-hydroxy for

in retinoid

3,4-didehydro-retinoic

by an isomerase-like enzyme (94). The latter reaction couples the free energy ofhydrolysis ofan ester to the thermodynamically uphill trans to cis isomerization, thus providing the energy to drive

products epidermis

nous

and to limit its bound to spe-

A in lipid to be the

normal

doses

vitamin increases

than the ofall-irans

to the direct

mediate

and

be important

hydroxyl

esterification.

times higher esterification

4-oxo

also

in excess

even more after retinoic acid injections (66). Furthermore, the high concentration ofCRBP(I) (the substrate carrier for LRAT) in stellate cells points to an important role of LRAT in stellate cell

may

acid

of them, enterocytes and mammary for transport to lymph and milk, re-

retinol to store vitamin above, LRAT seems

be important

glucuronides,

hydro-retinoic

or is esterified with long-chain fatty acids. conditions there are four major cell types

that esterify gland cells, cells, esterify As discussed

noyl acid, human

a hydrophilic

membranes.

disrupt

cific binding proteins Under physiological

cells.

retinol

metabolites may

BLOMHOFF

didehydro-retinol,

is a fat-soluble and

amounts,

may

4)

acid

of retinol

Retinol

enzyme

to active

3) retinoic

or retinal,

be catabolized

group,

may

acid

AND

but

manner. include

of cAMP-dependent and that

be independent

ribonucleotide some

The

number

important

of the of nuclear

that

of retinoylated

proteins protein

responses receptors

like

kinase

reductase

nuclear

via a thioester the regu(109).

cy-

(1 1 1). These

of cells having

to retinoic retinoids

VITAMIN Catabolism

of retinal

Several

investigators

analyzing

by

of retinol.

Many

of them that

retinol found

are

polar

(99). retinol

The

vivo.

in

the

catabolism

biliary,

metabolites

identified

to 4-hydroxy

be involved

studied

urinary.

more been

have

oxidize

have

radioactive

are

formed

and

retinol,

P-450

(1 12). Also

metabolites

of retinoic

the production

formed, retinoic The catabolism to retinoyl

system

[3-glucuronide

and

Many

in addition in nanomolar

all-trans acid,

retinoic and

acid,

all-trans

of vitamin ingestion

whether

systems

these

oxidation

epoxidation,

retinoic

retinoids

isom-

retinyl

and

acid,

in

nanomolar

depends

on the

reflect

retinoid

concentrations,

one

role

should

A action. in vitro

not

been

have

made

A metabolism for future study.

and function, For example,

olism

ofcarotenoids,

the mechanisms

ofretinoids

metabolism

and

proteins in vitamin

acterized,

an

proteins

that

topics

work

to provide

the

years

substances

it was therefore

and letter

in the alphabet

Soluble

and regulation

of retinoic

need to be studied involved

identified

in

retinol

retinol

cloned

and

been.

not

and

challenge

will

how

are

the cells),

they

during

Preliminary

and

ob-

retinoic

McCollum

described

totally

and

appropriate

to name

what

how

There

is little

A transport (both and action will stimulating and

in

Davis

19 1 5 were for them

they

had

that

Michael

H Green,

Berg, University ofOslo, made the present review

growth.

RM.

Postprandial

AA. Metabolism ofnatural retinoidsand their functions. T, ed. New trends in biological chemistry. Jpn Sci Soc

cleavage

H. Retinal

is not formed

of beta-carotene.

Biochemistry

gastrointestinal

E. Borgstrom in the

retinyl palmitate

disease.

Am

J Clin

Nutr

1992:55:

B. Intestinal absorption of retinol and rat. Effects of tetrahydrolipstatin. Lipids

1990:25:549-52.

19. Rigtrup

KM.

to the

20.

brush

Krasinski plasma use

21.

Ong DE. A retinyl

ester

border

of rat

Hazzard remnants

membrane

1783 (abstr). SD. Cohn iS, vitamin

of plasma

lomicrons

and

Russel

A metabolism retinyl

esters

their

remnants.

WR,

Bierman

following

l

disease (type 1976:25:777-801.

intellectual

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Chem

1965:54:1364-9.

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I 8. Fernandez

first

in the diet during

J Biol

857-64.

22.

factors

Sci USA

patients

State University,

and helpful

retinal.

into

16. Kakkad BP, Ong DE. Reduction of retinaldehyde bound to cellular retinol-binding protein (type II) by microsomes from rat small intestine. J Biol Chem 1988:263:12916-9. I 7. Johnson El, Krasinski SD, Howard U, Alger SA, Dutta 5K, Russell RM. Evaluation of vitamin A absorption by using oil-soluble and water-miscible vitamin A preparations in normal adults and in

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IS. Olson JA. Hayaishi 0. The enzymatic cleavage offi-carotene into vitamin A by soluble enzymes of rat liver and intestine. Proc NatI

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to

may

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