Download Nobel Prize for of Cholesterol

NEWS
IN PHYSIOLOGICAL
SCIENCES
Nobel Prize for
Cellular Uptake
of Cholesterol
Nobel Prize was made in 1973 when
The 1985 Nobel Prize in Physiologv or Medicine was awarded to Michael S. Brown and Joseph L. Goldstein for their discoveries concerning the regulation of cholesterol me-
tor-bound LDL enters the cell by en-
!X%of all myocardial infarcts. Famil-
docytosis. The LDL receptor is localized in the cell membrane
in socalled coated pits. After LDL has
been bound to the receptor, the
coated pit invaginates and pinches
off to form a coated vesicle. Several
vesicles thereafter fuse to form an
ial hypercholesterolemia
exists in
different forms and is inherited as a
monogenic dominant
trait. Individuals who carry the mutant gene in
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outer cell membranes
have specific
receptors for LDL and that the recep-
and Goldstein
the outer cell
in
the
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eases of genetic origin. It affects one
in 500 persons and is responsible for
pairs (homozygotes) are severely af-
fected. Their
serum
cholesterol
levels are five times higher than in
healthy persons, and severe athero-
endosome.
that mediate the uptake of the cholesterol-containing
particles, called
lipoprotein
low-density
(LDL),
which circulate in the blood. The
LDL endosome is then released inside the cell. The entire process is
called receptor-mediated
endocytosis.
sclerosis and coronary infarction are
seen already in adolescence. The
discovery that the cells in these patients lack LDL receptors or have a
LDL binds to the receptors and then
Too few LDL-receptors in the cell
membrane lead to a diminished LDL
uptake and an increased level of LDL
in the blood with subsequent risk of
accumulation in the arterial walls.
Using modern techniques, Brown
and Goldstein were able to show that
the LDL receptor is a glycoprotein
lower than normal density of these
lesterol is used by the cells for membrane formation and steroid hormone synthesis, and in addition it is
involved in the regulation of choles-
cholesterol
nf
VA
membranes carry specific receptors
enters the cell where its cholesterol
is liberated by lysosomes. The cho-
The
Familial
nno
VllV
receptors explains their high level of
LDL, causing it to build up in the
plasma and deposit in the arterial
mechanisms of cholesterol metabolism and have opened the possibili-
located in the cell membrane.
Its
protein part consists of 839 amino
acids; 767 of these are localized on
walls,
producing
atherosclerosis.
These discoveries have stimulated
research on the use of drugs, such as
cholestyramine
and menicholine,
to
increase the density of LDL receptors
in the cell membranes of these patients. Thus, to quote Brown and
ties for prevention
and treatment of
the cell surface, 22 in the interior of
Goldstein,
atherosclerosis and heart disease.
Cholesterol
has two main functions in the body. It is a structural
component in cell membranes, and
it is converted to certain hormones
and bile salts. More than XI% of the
cholesterol in the body is found in
the membrane, and 50 inside the cell
in the cytoplasm. When LDL is internalized
by endocytosis,
it suppresses the endogenous cholesterol
synthesis and stimulates
esterifaction of cholesterol. The LDL receptor
is recycled between lysosomes and
ble for many people to have their
steak and live to enjoy it too.”
cell
terol metabolism.
These discoveries
have given insight into the basic
membranes,
Cholesterol
is
“It may one day be possi-
By their work, Brown and Gold-
stein have made three fundamental
contributions:
z ) the demonstration
of cell surface receptors that mediate
the endocytosis of macromolecules;
the cell membrane for re-use.
2) the demonstration
stored in cells of the adrenals and
gonads where it is utilized for the
In their studies Brown and Goldstein used cultured
human fibro-
cally transmitted
defect in the LDL
receptor produces familial
hyper-
production
a geneti-
blasts. Like all other cells, the fibro-
cholesterolemia;
trogen, testosterone, and cortisone.
Cholesterol
also takes part in the
synthesis of vitamin D. Cholesterol
is transported
in blood and lym-
blasts need cholesterol for their cell
membranes. When studying the cholesterol metabolism
of fibroblasts
from patients suffering from familial
phatic fluid packeted into lipopro-
hypercholesterolemia,
Brown
teins. There are three kinds of lipoproteins classified on the basis of
Goldstein
found that
blasts lacked functional
these fibroLDL recep-
lation of the concept of receptor diseases.
These contributions
represent a
major
breakthrough
and clearly
qualify Brown and Goldstein for the
award they have received. Their discoveries have given new insight into
their
The particles that
cholesterol are the low-
density.
transport
density
of hormones such as es-
that
lipoproteins
The basic discovery
38
NIPS
1/February
tors, whereas patients with a milder
form
of
familial
hypercholesterol-
emia had a reduced number of LDL
receptors.
(LDL).
that led to the
Volume
and
1986
and
3) the
formu-
the mechanisms
underlying
the regulation
of cholesterol
metabolism
and the way the body utilizes
protein structures
to deliver
a specific
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tabolism.
In 1973 Brown
demonstrated
that
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U”IU~LUIII
30th International
Congress of
Physiological
Sciences
The 30th International
Congress of
Physiological
Sciences will be held
in Vancouver,
British
Columbia,
Canada, July 13-18, 1986. A brochure describing the Congress and
containing
registration
and abstract
forms has been mailed to more than
6,000 physiologists
who requested it.
Extra copies of these forms have
been made available
to national
physiological
societies.
The Congress will begin with an
opening ceremony in the Orpheum
Theatre in downtown
Vancouver,
followed by a reception in nearby
Robson Square on Sunday, July 13.
The following day the scientific sessions will begin on the campus of the
University
of British Columbia.
An
interesting
programme
of invited
lectures, symposia, and poster sessions has been arranged by the International
Programme
Committee.
The campus of the University
of
British Columbia is one of the most
beautiful in the world and provides
many attractions and a convenient
setting
for the Congress. Social
events during the week will include
the following: the Congress Concert
at which the Vancouver Bach Choir
will perform
Verdi’s Requiem,
a
banquet and entertainment,
and a
farewell barbecue. There will be opportunities
for day trips and cruises
to view the coastal scenery and Vancouver Island. In addition
to the
main scientific
programme,
there
will be historical lectures and an historical exhibit as well as workshops
on the teaching of physiology. The
Congress will also include a trade
exhibit. The closing ceremony
on
Friday July 18 at 6 P.M. will terminate the Congress.
From May to October 1986, Vancouver will be the site of Expo '86,
the largest special category exposition mounted in the Americas. This
will be an added attraction for visitors but also means that it is essential
to make reservations for travel and
accommodations
as early as possible.
The Organising
Committee
is
working hard to ensure that the Congress is highly successful and hopes
to welcome a large number of physiologists from all over the world to
Vancouver in 1986. For further information write to IUPS Secretariat,
(j/o Venue West Ltd., 801-750 Jervis
St., Vancouver, BC V6E 2A9, Canada
(Telex 04-352848 VCR).
Lung Collapse
During Free Diving
Total lung collapse in diving seals
was inferred by P. F. Scholander in
1940. He had noticed that seals exhale immediately
before diving; that
is, they don’t fill their lungs with air
as most of us would do before swimming underwater.
Scholander
also
correctly interpreted his observation
as a protective measure against the
bends, or decompression
sickness,
known to be caused by supersaturation of the blood and tissues with
nitrogen so that bubbles are formed
when pressure is again reduced.
The danger of repeated dives with
air-filled lungs was unintentionally
demonstrated by a human skindiver.
A Danish physician, P. Paulev, who
had practiced
underwater
escape
techniques in a 2O-m-deep training
tank, had dived repeatedly for 5 h,
using the drop technique.
In this
method
the diver, after a deep
breath, pushes himself downward,
and after he has descended 2 or 3 m,
his chest is compressed so that he
continues to drop to the bottom with
increasing
speed. After 60 such
dives, each lasting about 2 min, Dr.
Paulev developed pain in the joints,
breathing difficulties, blurred vision,
and abdominal
pains. He was saved
when a colleague found him in impending shock, rapidly diagnosed his
condition,
and placed him in a recompression
chamber
where the
symptoms disappeared.
There is now direct evidence that
seals indeed avoid the danger of repeated dives by lung collapse, as
Scholander
inferred.
An international team of nine scientists obtained arterial blood samples from
diving Weddell
seals during free
dives that lasted up to 23 min at
depths up to 230 m. The seals were
instrumented
to obtain blood samples during the dives, and these
showed that nitrogen uptake is effectively stopped by the collapse of gasexchanging alsveoli at a depth of approximately
28 m (3.7 atm absolute
pressure). At this depth the major
fraction of the seal’s lung gas is compressed into nonexchanging
seg-
Downloaded from http://physiologyonline.physiology.org/ by 10.220.33.4 on August 9, 2017
metabolite,
in this case cholesterol
for membrane synthesis and for production of steroid hormones.
The two Nobel Prize winners are
from the same research institution,
the Department
of Molecular
Genetics, University
of Texas Health
Science Center at Dallas, TX, where
they carried out the work that today
merits them the highest possible international
esteem in science.
Michael
S. Brown was born in
1941 in New York. After receiving
his BS and MD degrees at the University of Pennsylvania
and after
two years as intern and resident in
medicine at Massachusetts General
Hospital in Boston, he moved to Bethesda to work at the National Institute of Arthritis and Metabolic Diseases and later at the National Heart
Institute. In 1971 he was appointed
Assistant Professor of Medicine
at
the University
of Texas Southwestern Medical School, where in 1977
he became Paul J. Thomas Professor
of Genetics and Director of the Center of Genetic Disease.
Joseph L. Goldstein was born in
1940 in Sumter, SC. He received his
BS degree in 1962 at Washington and
Lee University and his MD degree in
1966 at the University
of Texas
Southwestern
Medical School, Dallas, After interning at Massachusetts
General Hospital and working at National Institutes of Health and University of Washington
School of
Medicine in Seattle, he became, in
1972, head of the Division of Medical
Genetics at the University
of Texas
Health Science Center, where in
1977 he was appointed
Paul J.
Thomas Professor of Medicine
and
Genetics.
David Ottoson
Karolinska Institutet
Volume 1/February
1986
NIPS
39
merits 01 the respiratorI,
tract, thus
csff~v tivclty preventing
entry of nitrogen into thrs blood.
(Rcfcrvncp:
Seal lungs collapse:
during frrp diving: c~~~idencc from
drteri,il
nitrogen
tensions
scl~~nct~
I\‘wh. Lx: 229: 5.50-5~8.
1~185 ]
h.
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N.
Opposite Effects
of Opioids in
Brain and Periphery
40
NE’S
Volume I /February 1986
I
&fICLE
2 ON READER
SERVICE
it
314:
533-534.
1985.3
K. LlcN.
The
hdoduhrph~rcal
leetwesoverm
r
(:ross the blood-brain
barrier. proved
to hav(:
positive reinforcing
effect.
suggc:stirlg that the airersive effect of
naltresone
\vas dut: tn blocking
of
central olliate receptors.
Other CSperiments are in agreement with the
cmnclusion that the aversive: effects
of opiates arc! peripheral and are carried in the vag~s nerve from the
Iwriphery
(thv gut) to the tlrain.
Lvhereas the I)ositi\rc? reinforcing
or
t:uphoric effm:ts are caused bv direct
ac:tion ori central brain receptors.
The investigatnrs
suggest that attc*rnpts at blocking
the peripheral
opiate receptors
may open an il\‘f?nuf:
for combating
the: adversiirct r:ffccts nf opiates on human patients
lvho receive opiates for pain relief.
(Kr:fr:rc:uce: Opposite moti~~ational
effects
of endogenous
opioids in
brain and peripher!..
Sulurc: I,ofld.
intertace is Mty implemented
lof
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CARD
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In humans the euphoric: or positive reinforcing
effects of opiates are
well knoivn to recreational
users as
well as addicts. yet, when opiates arc:
used for pain c:ontrol. the effects art:
often negative anal
include nausea.
I\ similar paradoxical
effect has been
demonstrated
in rats. \‘Vhen paired
Lvith visual environmental
stimuli.
opiatf?s produce positive
reinforcement in rats but similar doses ad-
minlstarcvi
in idvnt ic.dl Idshlon produc:~ ,1\.ersive effects xvhcn [kiirfxl
l<rith t,l\tt> stimuli
,L\ r~wlution
of these pdrCldoxi( ,I]
rffrc ts may nolv be close. I>rs. Bt:c.hara
2nd
sari
clcr
Koov
of the l’nivarsity of Toronto
report that both
r~ndogcnous
dnd exogenous
opioids
produce positive
rvlnfrlrc ing effects
through
action on braIn re( eptors
but produ( e avcrsivc> vffvc ts through
dLtion on peripheral
rrxxptors.
~‘5
pw.idllv III the gut.
‘I’htl t~ulwriments
lverr designed to
ohstlrvv positive and negative c,fft:c ts
on
bc:h,lr.ioral prefcrcnces
of r,jts. ‘1’0
distinguish
brtwePn
the opiate cffacts on t)r,tin
receptors and periphcral receptors, the rats tvere injected
\vith naltreuone
or its derivative
Ineth~lnaltrc,xontl.
Ndltrekone.
well
AIIOIVII
ns A t)lnt
kt:r of the euphoric
effects of oplatw.
rrdclil\* ( rosses the
blood-brain
barrier and had an aversive effect on the: rdts. Thv methyl
derivative.
Lvhich dot5
not readily