Nature Communications,
Год журнала:
2016,
Номер
7(1)
Опубликована: Ноя. 28, 2016
Abstract
Despite
widespread
use
of
statins
to
reduce
low-density
lipoprotein
cholesterol
(LDL-C)
and
associated
atherosclerotic
cardiovascular
risk,
many
patients
do
not
achieve
sufficient
LDL-C
lowering
due
muscle-related
side
effects,
indicating
novel
treatment
strategies
are
required.
Bempedoic
acid
(ETC-1002)
is
a
small
molecule
intended
lower
in
hypercholesterolemic
patients,
has
been
previously
shown
modulate
both
ATP-citrate
lyase
(ACL)
AMP-activated
protein
kinase
(AMPK)
activity
rodents.
However,
its
mechanism
for
lowering,
efficacy
models
atherosclerosis
relevance
humans
unknown.
Here
we
show
that
ETC-1002
prodrug
requires
activation
by
very
long-chain
acyl-CoA
synthetase-1
(ACSVL1)
targets,
inhibition
ACL
leads
LDL
receptor
upregulation,
decreased
attenuation
atherosclerosis,
independently
AMPK.
Furthermore,
demonstrate
the
absence
ACSVL1
skeletal
muscle
provides
mechanistic
basis
potentially
avoid
myotoxicity
with
statin
therapy.
Physiological Reviews,
Год журнала:
2018,
Номер
98(4), С. 2133 - 2223
Опубликована: Авг. 1, 2018
The
1921
discovery
of
insulin
was
a
Big
Bang
from
which
vast
and
expanding
universe
research
into
action
resistance
has
issued.
In
the
intervening
century,
some
discoveries
have
matured,
coalescing
solid
fertile
ground
for
clinical
application;
others
remain
incompletely
investigated
scientifically
controversial.
Here,
we
attempt
to
synthesize
this
work
guide
further
mechanistic
investigation
inform
development
novel
therapies
type
2
diabetes
(T2D).
rational
such
necessitates
detailed
knowledge
one
key
pathophysiological
processes
involved
in
T2D:
resistance.
Understanding
resistance,
turn,
requires
normal
action.
review,
both
physiology
pathophysiology
are
described,
focusing
on
three
target
tissues:
skeletal
muscle,
liver,
white
adipose
tissue.
We
aim
develop
an
integrated
physiological
perspective,
placing
intricate
signaling
effectors
that
carry
out
cell-autonomous
response
context
tissue-specific
functions
generate
coordinated
organismal
response.
First,
section
II,
effects
direct,
tissue
reviewed,
beginning
at
receptor
working
downstream.
Section
III
considers
critical
underappreciated
role
crosstalk
whole
body
action,
especially
essential
interaction
between
lipolysis
hepatic
gluconeogenesis.
is
then
described
IV.
Special
attention
given
pathways
become
resistant
setting
chronic
overnutrition,
alternative
explanation
phenomenon
‟selective
resistanceˮ
presented.
Sections
V,
VI,
VII
critically
examine
evidence
against
several
putative
mediators
V
reviews
linking
bioactive
lipids
diacylglycerol,
ceramide,
acylcarnitine
resistance;
VI
impact
nutrient
stresses
endoplasmic
reticulum
mitochondria
discusses
non-cell
autonomous
factors
proposed
induce
including
inflammatory
mediators,
branched-chain
amino
acids,
adipokines,
hepatokines.
Finally,
VIII,
propose
model
links
these
final
common
metabolite-driven
gluconeogenesis
ectopic
lipid
accumulation.
Diabetologia,
Год журнала:
2017,
Номер
60(9), С. 1577 - 1585
Опубликована: Авг. 3, 2017
Metformin
is
a
widely-used
drug
that
results
in
clear
benefits
relation
to
glucose
metabolism
and
diabetes-related
complications.
The
mechanisms
underlying
these
are
complex
still
not
fully
understood.
Physiologically,
metformin
has
been
shown
reduce
hepatic
production,
yet
all
of
its
effects
can
be
explained
by
this
mechanism
there
increasing
evidence
key
role
for
the
gut.
At
molecular
level
findings
vary
depending
on
doses
used
duration
treatment,
with
differences
between
acute
chronic
administration.
act
via
both
AMP-activated
protein
kinase
(AMPK)-dependent
AMPK-independent
mechanisms;
inhibition
mitochondrial
respiration
but
also
perhaps
glycerophosphate
dehydrogenase,
involving
lysosome.
In
last
10
years,
we
have
moved
from
simple
picture,
improves
glycaemia
acting
liver
AMPK
activation,
much
more
picture
reflecting
multiple
modes
action.
More
work
required
truly
understand
how
works
target
population:
individuals
type
2
diabetes.
Medical Principles and Practice,
Год журнала:
2015,
Номер
24(5), С. 401 - 415
Опубликована: Янв. 1, 2015
The
anti-diabetic
and
oral
hypoglycaemic
agent
metformin,
first
used
clinically
in
1958,
is
today
the
choice
or
‘gold
standard'
drug
for
treatment
of
type
2
diabetes
polycystic
ovary
disease.
Of
particular
importance
diabetes,
metformin
affords
protection
against
diabetes-induced
vascular
In
addition,
retrospective
analyses
suggest
that
with
provides
therapeutic
benefits
to
patients
several
forms
cancer.
Despite
almost
60
years
clinical
use,
precise
cellular
mode(s)
action
remains
controversial.
A
direct
indirect
role
adenosine
monophosphate
(AMP)-activated
protein
kinase
(AMPK),
fuel
gauge
cell,
has
been
inferred
many
studies,
evidence
activation
AMPK
may
result
from
a
mild
inhibitory
effect
on
mitochondrial
complex
1,
which
turn
would
raise
AMP
activate
AMPK.
Discrepancies,
however,
between
concentrations
vitro
studies
versus
levels
caution
should
be
applied
before
extending
inferences
derived
cell-based
seen
patients.
Conceivably,
effects,
some
them,
at
least
partially
independent
and/or
respiration
reflect
either
minor
and,
as
yet,
unidentified
putative
metabolite
target
protein(s)/signalling
cascade.
this
review,
we
critically
evaluate
data
have
investigated
pharmacokinetic
properties
basis
hypoglycaemic,
insulin-sensitising
protective
effects
metformin.
