Download LIGHT Hits the Liver

PERSPECTIVES
MEDICINE
An inflammatory molecule on the surface
of certain immune cells increases the
concentration in blood of fats associated
with atherosclerosis.
LIGHT Hits the Liver
Göran K. Hansson
A
The author is in the Department of Medicine and Center
for Molecular Medicine, Karolinska Institute, Stockholm,
SE-17176, Sweden. E-mail: [email protected]
206
LIVER
T CELL
Triglycerides
LIGHT
Very-low-density
lipoproteins
Fatty acids
Intermediatedensity lipoproteins
Hepatic
lipase
Chylomicron
remnant
Low-density
lipoproteins
INTESTINE
ARTERY
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Fatty acids
Chylomicron
Atherosclerosis
Lipolysis in the liver. Lipoproteins called chylomicrons and very-low-density lipoproteins transport triglycerides and cholesterol in the blood. Hepatic lipase assists in the receptor-mediated uptake of these lipoproteins into the liver. Triglycerides are hydrolyzed, releasing free fatty acids. Remaining very-low-density
lipoproteins can be converted into low-density lipoproteins that accumulate in arteries and initiate atherosclerosis. T cells expressing LIGHT inhibit hepatic lipase expression in hepatocytes, which causes increased
plasma lipoprotein concentrations, and may contribute to atherosclerosis.
OX40L, are involved in atherosclerosis, and
seem to propagate plaque inflammation (7, 8).
In contrast to tumor necrosis factor, LIGHT
is mainly expressed on the surface of T cells
and specialized cells of the immune system
called dendritic cells (9). Lo et al. observed
that transgenic mice engineered to overexpress
LIGHT on T cells developed hyperlipidemia,
displaying elevated cholesterol and triglyceride concentrations in the blood. When T cells
from such mice were transferred into normal
mice, plasma cholesterol concentration increased substantially. LIGHT (and lymphotoxin) bind to the lymphotoxin β receptor but
also to other receptors. By treating mice with
soluble forms of the receptor, to function as
“decoys,” the authors establish that the hyperlipidemic effect of LIGHT depends on the
lymphotoxin β receptor.
At first glance, it is remarkable that a cell
surface molecule expressed by T cells has
such dramatic effects on plasma lipids and
lipoproteins. However, other links between
cellular immunity and lipid homeostasis have
been uncovered. In atherosclerosis, T cells
of the T helper 1 subtype are activated by lipoproteins trapped in plaques on artery walls,
thus promoting inflammation (10). Natural killer
T cells, a subset of T cells, recognize lipids
13 APRIL 2007
VOL 316
SCIENCE
Published by AAAS
that are displayed in a complex with CD1
molecules on the surface of antigen-presenting cells (11). These T cells accelerate atherosclerosis (12) and are enriched in the liver. In
the Lo et al. study, treatment with soluble lymphotoxin β receptor did not affect plasma cholesterol concentration in mice lacking functional natural killer T cells. This subset of T
cells may conceivably regulate lipid homeostasis by delivering LIGHT to the liver (see
the figure).
The molecular mechanism by which the
lymphotoxin β receptor causes hyperlipidemia was explored by gene-expression
arrays. Lo et al. found a dramatic, 20-fold
decrease in messenger RNA that encodes the
enzyme hepatic lipase in the liver of transgenic mice that overexpress LIGHT on T
cells. Hepatic lipase activity was also reduced
in such mice, but not in transgenic mice that
overexpress LIGHT but lack the lymphotoxin
β receptor. When normal hepatocytes were
exposed to recombinant LIGHT or to T cells
overexpressing LIGHT, hepatic lipase expression dropped substantially.
Hepatic lipase is expressed on the surface of
hepatocytes in the liver. It promotes the receptor-mediated uptake of plasma lipoproteins that
harbor triglycerides and cholesterol and specif-
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CREDIT: P. HUEY/SCIENCE
therosclerosis, the underlying cause
of most cases of myocardial infarction, stroke, and gangrene, is the most
common lethal disease in Western societies
and is expected to become the number one
killer globally by 2020 (1). It is an inflammatory disease triggered by the accumulation of
plasma lipoproteins in the artery wall (2). In
this scenario, lipids cause inflammation.
However, a report by Lo et al. on page 285 in
this issue (3) turns the situation upside-down
by showing that two factors produced by
immune cells—the cytokines lymphotoxin
and LIGHT—cause the amount of lipids in
the blood to increase.
Several studies have implicated the tumor
necrosis factor superfamily of proinflammatory cytokines in lipid metabolism. Tumor
necrosis factor was discovered not only as
a soluble protein that induces the death
of tumor cells but also as a molecule
(cachectin) that causes hypertriglyceridemia
and wasting of muscle and fat tissue (4).
These effects are due to its inhibition of the
enzyme lipoprotein lipase, thus limiting the
supply of fatty acids for energy production
and fat storage. These remarkable metabolic
effects of this cytokine did not attract as
much attention as its proinflammatory
actions and its ability to promote cell death.
However, recent findings of tumor necrosis
factor secretion from adipose tissue of individuals with metabolic syndrome, a condition predisposing to atherosclerosis, have
focused much interest on the metabolic
action of this cytokine and its cousins (5).
Several of the more than 40 members of
the tumor necrosis factor superfamily of proinflammatory molecules are soluble cytokines;
others are membrane proteins that can ligate
receptors on adjacent cells. There is substantial
cross-talk between receptors and ligands. Two
members of this family, lymphotoxin and
LIGHT, share many features with tumor necrosis factor (the prototypic family member), such
as promoting inflammation and host defense
against pathogens, and they have been implicated in several inflammatory diseases, including rheumatoid arthritis and Crohn’s disease
(6). Two other superfamily members, CD40 and
PERSPECTIVES
ically catalyzes hydrolysis of the triglycerides
(13) (see the figure). Both these actions likely
contribute to the reduction in the amounts of
plasma lipids and lipoproteins observed when
LIGHT signaling is blocked by treatment with
soluble lymphotoxin β receptor.
The functional role of T cell–dependent
control of lipid homeostasis through hepatic
lipase is unclear. Perhaps inhibition of lipolysis reduces the amount of energy-rich compounds available to pathogens and/or redistribute fatty acids to other organs during host
defense. Studies of infections in mice lacking
the LIGHT–lymphotoxin β receptor–hepatic
lipase axis may provide interesting answers to
these questions.
Lo et al. suggest the exciting prospect
that increasing hepatic lipase expression
with agents that modulate LIGHT signaling
may represent a new therapy for treating of
dyslipidemia. It is even possible that inhibition of signaling by the lymphotoxin β
receptor could dampen atherosclerosis
by improving lipid metabolism as well as
by reducing vascular inflammation. In
humans, low hepatic lipase activity is associated with increased risk for atherosclerotic heart disease (14). However, proatherogenic as well as antiatherogenic
effects of hepatic lipase have been observed,
both in humans and in experimental animal
models, and its biology is not yet fully
understood (13). Further studies on the
metabolic and cardiovascular actions of
lymphotoxin, LIGHT, and related family
members are awaited with great interest.
References
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10.1126/science.1142238
CHEMISTRY
Femtosecond Lasers for Molecular
Measurements
Ultrafast spectroscopic techniques are finding
new applications in molecular detection.
Robert P. Lucht
hemists and biomedical researchers
are now using femtosecond lasers to
detect and measure molecules in an
increasing number of experiments (1–4). This
is driven by the commercial availability of
reliable laser systems with pulse lengths on
the order of 100 fs, fast repetition rates, and
high energy in each pulse. Taking advantage
of methods for producing a wide range of
photon wavelengths, researchers can now
expand their use of sophisticated spectroscopic detection techniques. On page 265 of
this issue, Pestov et al. (5) report the detection of Bacillus subtilis spores (a surrogate for
anthrax). In doing so, the authors have not
only targeted a substance of vital interest but
have advanced the wider use of femtosecond
spectroscopy for rapid and selective detection.
One of the most powerful techniques for
molecular detection is coherent anti-Stokes
Raman spectroscopy (CARS). In this method,
depicted schematically in the figure, two laser
pulses (historically called the pump and
Stokes pulses) create a coherent excitation of
molecules (called the Raman coherence) in
the sample at time t0. A third probe pulse interacts with this coherent state at time t1, creating
a signal (the anti-Stokes pulse) that can be
C
The author is in the School of Mechanical Engineering,
Purdue University, 585 Purdue Mall, West Lafayette, IN
47907–2088, USA. E-mail: [email protected]
used to map out the molecular resonances that
identify a particular chemical species.
Spectroscopists have used CARS with
nanosecond lasers for decades (6). Typically,
the technique relies on pulsed lasers with repetition rates of 10 Hz. Femtosecond laser systems offer the potential for drastic improvements in the capabilities of CARS diagnostic
systems. Data acqusition rates of 1 kHz or
greater can be achieved, provided that a CARS
signal can be acquired with every laser pulse.
Femtosecond laser systems also offer the
potential to minimize the nonresonant back-
ground and eliminate the effects of molecular
collisions on CARS signal generation.
Pestov et al. describe a hybrid CARS technique in which a 50-fs pump and Stokes
pulses are used to induce a Raman coherence
in a target molecule. A “shaped” probe pulse
is used that has a much narrower bandwidth and, consequently, a much longer pulse
length. As discussed by Pestov et al., the
Fourier-transform-limited pump and Stokes
pulses (that is, minimum duration for their
spectral bandwidth) are optimal for excitation
of the Raman coherence. In terms of probing
Pump beam
675 nm, 200 cm–1
E
E
E
Ωpump
ΩStokes
Ωprobe
ΩCARS
2330 cm–1
E
2330 cm
–1
2330 cm–1
2330 cm–1
E
G
G
t0
t1
G
G
G
Stokes beam
A coherent picture. (Left) Creation of the Raman
800 nm, 200 cm–1
coherence at time t0 and scattering of the probe
Optical frequency
beam to generate the CARS signal at t1. (Right)
Schematic illustration of the pump-Stokes frequency pairs that contribute to the excitation of the Raman coherence for Q-branch transitions in the 2330
cm–1 vibrational band of N2.
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SCIENCE
VOL 316
Published by AAAS
13 APRIL 2007
207
LIGHT Hits the Liver
Göran K. Hansson
Science 316, 206 (2007);
DOI: 10.1126/science.1142238
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