The document summarizes research on lymphatic transport of lipid. It finds that the lymphatics play a key role in lipid uptake and movement. Abnormal lipid accumulation is seen in lymphatic disease and can be modeled in animals. Importantly, a fraction of lipid is transported via an active, transcellular route rather than passively diffusing through the lymphatic vessel walls. Further research aims to elucidate the molecular mechanisms of lymphatic lipid transport and optimize drug delivery strategies targeting the lymphatics.
2. Func;ons
of
the
lympha;c
system
• Tissue
fluid
balance
• Immune
cell
trafficking
• Lipid
uptake
– Peripheral
– Intes;nal
Pepper
MS
and
Skobe
M
(2003)
J
Cell
Biol
163(2):209-‐213
3. Structure
of
the
lympha;c
system
• Peripheral
dermal
lympha;cs
• Lympha;c
vessels
made
up
of
endothelial
cells
(LECs)
• LECs
connected
via
specialized
junc;ons
Alitalo
K
et
al.
(2005)
Nature
438:946-‐953
5. Intes;nal
lympha;c
dysfunc;on
• Chylous
ascites:
leakage
of
lipid
into
abdominal
cavity
• Acquired
or
congenital
• Draining
and
dietary
management
• Leakage
may
also
occur
in
thoracic
cavity
and
around
the
heart
in
lymphangiomatosis.
Dietrich
S
et
al.
(2009)
Case
Rep
Oncol
2(2):144-‐149
Herman
TE
and
Sigel
MJ
(2009)
J
Perinatol
29:178-‐180
6. Inherited
lymphedema
and
other
lympha;c
disorders
• Result
from
rare,
inherited
chromosomal
disorders
or
muta;ons
• Malforma;ons
of
the
lympha;cs
• Mul;-‐factorial,
systemic
diseases
Alders
M
et
al.
(2012)
Mol
Syndromol
4:107-‐113
7. Abnormal
lipid
accumula;on
is
a
feature
of
secondary
lymphedema
Courtesy
of
H.
Brorson,
MD
“Lymphedema
is
regional
obesity.”
-‐
Babak
J.
Mehrara,
MD
8. Animal
model
of
lympha;c
dysfunc;on
Many
mice
died
with
chylous
ascites
in
the
abdominal
and
thoracic
cavi;es
soon
aYer
birth.
Increased
subcutaneous
fat
deposits
and
larger
adipocytes
were
observed
in
the
skin.
Mice
that
survived
became
obese
as
they
reached
adulthood
and
had
elevated
insulin
and
lipid
in
the
liver.
Harvey
NL
et
al.
(2005)
Nature
Gene>cs
37(10):1072-‐1081
9. Animal
model
of
lymphedema
Zampell
JC
et
al.
(2012)
Plas>c
and
Rec
Surg
129(4):825-‐834
Lipid
accumulated
in
;ssue
in
lymphedema
condi;on.
11. Toward
a
;ssue
engineered
lacteal
Dixon
JB
et
al.
(2009)
Biotechnol
and
Bioeng
103(6):1224-‐1235
12. Further
evidence
of
ac;ve
transport
• The
lympha;cs
clear
cholesterol
from
the
peripheral
;ssue
space.
• Transport
is
specific
and
transcellular.
• This
process
helps
maintain
cholesterol
levels
and
prevents
atherosclerosis.
Lim
HY
et
al.
(2013)
Cell
Metab
17(5):671-‐684
13. Experimental
objec;ve
• To
inves;gate
the
ac;ve
component
of
lympha;c
lipid
transport
and
its
rela;ve
importance
to
overall
uptake
using
in
vitro
models
of
the
peripheral
lympha;cs
and
the
enterocyte-‐lacteal
interface.
14. Transcellular
lipid
transport
0 mM 10 mM
100
80
60
40
20
0
NaN3 Concentration
% flux of control
*
LECs
growing
on
permeable
membrane
Apical
compartment
from
which
sample
was
collected
and
fluorescence
measured
Basolateral
compartment
containing
albumin-‐bound
bodipy
and
dextran
Transcellular
transport
of
fluorescent
lipid
was
inhibited
when
cellular
fuel
was
depleted,
sugges;ng
transport
is
ac;ve.
15. Chylomicron
transport
*
0 mM 2 mM 5 mM 10 mM
0.20
0.15
0.10
0.05
0.00
Peff (μm/sec)
NaN3 concentration
*
*
0 mM 2 mM 5 mM 10 mM
100
80
60
40
20
0
NaN3 concentration
% flux of control
*
* *
Total
and
transcellular
transport
of
chylomicrons
was
significantly
reduced
when
cellular
fuel
was
depleted,
sugges;ng
both
these
process
are
ac;ve,
par;cularly
transcellular
transport.
17. Summary
• The
lympha;cs
play
a
pivotal
role
in
lipid
uptake
and
movement.
• Abnormal
lipid
accumula;on
is
a
feature
of
lympha;c
disease
and
can
be
modeled
in
animals.
• An
important
frac;on
of
lipid
is
transported
via
an
ac;ve,
transcellular
route.
18. Future
direc;ons
• Elucida;ng
the
molecular
mechanisms
of
transport.
• Op;mizing
drug
delivery
strategies
to
target
the
lympha;cs.
– Encapsula;ng
a
chemotherapeu;c
agent
resulted
in
increased
efficacy
in
the
blood
via
lympha;c
uptake
and
delivery
(Ali-‐Qadri
et
al.
(2013)
PNAS
Early
Ed.
19. Acknowledgements
• NIH
R00HL091133
• Sydney
Rowson
• Pe;t
Undergraduate
Research
Scholars
Program
Mentorship
Funds
• Timothy
Kassis
• John
McDonald
lab
