Hepatology Communications,
Journal Year:
2024,
Volume and Issue:
9(1)
Published: Dec. 19, 2024
Primary
biliary
cholangitis
(PBC)
and
primary
sclerosing
(PSC)
are
characterized
by
the
destruction
of
small
bile
ducts
formation
multifocal
strictures,
respectively,
impairing
flow.
This
leads
to
hepatic
accumulation
acids,
causing
liver
injury
risk
progression
cirrhosis
failure.
First-line
therapy
for
PBC
is
ursodeoxycholic
acid,
although
up
40%
treated
individuals
incomplete
responders,
there
no
effective
PSC,
highlighting
need
better
therapeutic
options
in
these
diseases.
In
addition,
pruritus
a
common
symptom
cholestasis
that
has
severe
consequences
quality
life
often
undertreated
or
untreated.
Nuclear
receptors
pharmacological
targets
treat
due
their
multifactorial
regulation
enzymatic
pathways,
particularly
acid
metabolism.
The
peroxisome
proliferator-activated
receptor
(PPAR)
significant
clinical
interest
its
role
regulating
synthesis
detoxification
pathways.
PPAR
agonism
fibrates
traditionally
been
explored
PPARα’s
expression
liver;
however,
recent
expanded
focus
on
newer
agonists
activate
other
isoforms,
example,
δ,
γ,
alone
combination.
Several
have
investigated
as
second-line
people
living
with
PBC,
including
accelerated
United
States
Food
Drug
Administration
approval
elafibranor
seladelpar.
review
evaluates
available
data
efficacy
safety
five
treatment
associated
namely
fenofibrate,
bezafibrate,
saroglitazar,
elafibranor,
New England Journal of Medicine,
Journal Year:
2024,
Volume and Issue:
390(9), P. 783 - 794
Published: Feb. 21, 2024
Effective
treatments
for
patients
with
primary
biliary
cholangitis
are
limited.
Seladelpar,
a
peroxisome
proliferator-activated
receptor
delta
agonist,
has
potential
benefits.
Biomolecules,
Journal Year:
2023,
Volume and Issue:
13(8), P. 1264 - 1264
Published: Aug. 18, 2023
The
number
of
patients
with
nonalcoholic
fatty
liver
disease
(NAFLD)/nonalcoholic
steatohepatitis
(NASH)
is
increasing
globally
and
raising
serious
concerns
regarding
the
medical
economic
burden
incurred
for
their
treatment.
progression
NASH
to
more
severe
conditions
such
as
cirrhosis
hepatocellular
carcinoma
requires
transplantation
avoid
death.
Therefore,
therapeutic
intervention
required
in
stage,
although
no
drugs
are
currently
available
this.
Several
anti-NASH
candidate
have
been
developed
that
enable
treatment
via
modulation
distinct
signaling
cascades
include
a
series
targeting
peroxisome
proliferator-activated
receptor
(PPAR)
subtypes
(PPARα/δ/γ)
considered
be
attractive
because
they
can
regulate
both
systemic
lipid
metabolism
inflammation.
Multiple
PPAR
dual/pan
agonists
but
only
few
them
evaluated
clinical
trials
NAFLD/NASH.
Herein,
we
review
current
trial
status
future
prospects
PPAR-targeted
treating
In
addition,
summarize
our
recent
findings
on
binding
modes
potencies/efficacies
several
estimate
potentials
against
NASH.
Considering
development
numerous
has
abandoned
side
effects,
also
propose
repositioning
already
approved,
safety-proven
Biomedicines,
Journal Year:
2024,
Volume and Issue:
12(3), P. 624 - 624
Published: March 11, 2024
Three
peroxisome
proliferator-activated
receptor
subtypes,
PPARα,
PPAR(ß/)δ,
and
PPARγ,
exert
ligand-dependent
transcriptional
control
in
concert
with
retinoid
X
receptors
(RXRs)
on
various
gene
sets
harboring
PPAR
response
elements
(PPREs)
their
promoter
regions.
Ligand-bound
PPAR/RXR
complexes
do
not
directly
regulate
transcription;
instead,
they
recruit
multiprotein
coactivator
to
specific
genomic
regulatory
loci
cooperatively
activate
transcription.
Several
coactivators
are
expressed
a
single
cell;
however,
ligand-bound
can
be
associated
only
one
through
consensus
LXXLL
motif.
Therefore,
altered
transcription
induced
by
subtypes/agonists
may
attributed
the
recruitment
of
species.
Using
time-resolved
fluorescence
resonance
energy
transfer
assay,
we
analyzed
four
peptides
(PGC1α,
CBP,
SRC1,
TRAP220)
human
PPARα/δ/γ-ligand-binding
domains
(LBDs)
using
eight
dual/pan
agonists
(bezafibrate,
fenofibric
acid,
pemafibrate,
pioglitazone,
elafibranor,
lanifibranor,
saroglitazar,
seladelpar)
that
are/were
anticipated
treat
nonalcoholic
fatty
liver
disease.
These
all
recruited
PPARα/γ-LBD
varying
potencies
efficacy.
Only
five
PPARδ-LBD,
concentration-dependent
responses
differed
from
those
PPARα/γ-LBD.
results
indicate
expression
PPREs
different
caused,
part,
coactivators,
which
responsible
for
unique
pharmacological
properties
these
agonists.
npj Metabolic Health and Disease,
Journal Year:
2024,
Volume and Issue:
2(1)
Published: July 3, 2024
Abstract
Nuclear
receptors
(NRs)
regulate
cellular
processes
and
serve
as
key
targets
in
treating
metabolic
dysfunction-associated
steatotic
liver
disease
(MASLD)
steatohepatitis
(MASH).
Their
ability
to
interact
influence
each
other’s
signaling
pathways
introduces
a
complex
yet
underexplored
dimension
the
pharmacotherapy
of
MASLD
MASH.
This
review
delineates
emerging
NRs
this
field—estrogen-related
receptor
alpha
(ERRα),
glucocorticoid
(GR),
estrogen
(ERα),
homolog-1
(LRH-1),
vitamin
D
(VDR)—and
their
interplay
with
established
NRs,
including
peroxisome
proliferator-activated
(PPARα,
PPARβ/δ,
PPARγ),
farnesoid
X
(FXR),
(LXR),
hepatocyte
nuclear
factor
4α
(HNF4α),
thyroid
hormone
beta
(THRβ).
We
discuss
collective
impact
on
hepatic
lipid
metabolism,
inflammation,
fibrosis,
glucose
homeostasis.
explore
recent
findings
dual
NR
crosstalk,
via
direct
indirect
mechanisms,
potential
targeting
using
selective
agonists,
inverse
antagonists,
or
specific
modulators
combat
Elucidating
interactions
opens
up
new
avenues
for
targeted
therapies,
emphasizing
critical
need
further
research
evolving
field
hepatology.
Expert Opinion on Therapeutic Patents,
Journal Year:
2024,
Volume and Issue:
34(1-2), P. 83 - 98
Published: Feb. 1, 2024
The
search
for
novel
compounds
targeting
Peroxisome
Proliferator-Activated
Receptors
(PPARs)
is
currently
ongoing,
starting
from
the
previous
successfully
identification
of
selective,
dual
or
pan
agonists.
In
last
years,
researchers'
efforts
are
mainly
paid
to
discovery
PPARγ
and
δ
modulators,
both
agonists
antagonists,
selective
with
a
dual-multitarget
profile.
Some
these
under
clinical
trials
treatment
primary
biliary
cirrhosis,
nonalcoholic
fatty
liver
disease,
hepatic,
renal
diseases.
Clinical Science,
Journal Year:
2024,
Volume and Issue:
138(7), P. 435 - 487
Published: April 1, 2024
Abstract
Patients
with
inflammatory
liver
diseases,
particularly
alcohol-associated
disease
and
metabolic
dysfunction-associated
fatty
(MAFLD),
have
higher
incidence
of
infections
mortality
rate
due
to
sepsis.
The
current
focus
in
the
development
drugs
for
MAFLD
is
resolution
non-alcoholic
steatohepatitis
prevention
progression
cirrhosis.
In
patients
cirrhosis
or
alcoholic
hepatitis,
sepsis
a
major
cause
death.
As
center
key
immune
tissue,
guardian,
modifier,
target
Septic
dysfunction
highest
compared
other
organ
dysfunctions.
addition
maintaining
homeostasis,
produces
secretes
hepatokines
acute
phase
proteins
(APPs)
essential
tissue
protection,
immunomodulation,
coagulation.
Inflammatory
diseases
profound
disorder
impairment
energy
metabolism,
regeneration,
production/secretion
APPs
hepatokines.
Herein,
author
reviews
roles
(1)
disorders
metabolism
glucose,
acids,
ketone
bodies,
amino
acids
as
well
clearance
ammonia
lactate
pathogenesis
sepsis;
(2)
cytokines/chemokines
(3)
protection
against
injury
infections;
(4)
nuclear
receptors/signaling
pathways
underlying
injuries
drug
targets
Approaches
that
on
regeneration
will
not
only
treat
but
also
prevent
severe
Current Issues in Molecular Biology,
Journal Year:
2024,
Volume and Issue:
46(7), P. 6300 - 6314
Published: June 21, 2024
With
around
one
billion
of
the
world's
population
affected,
era
metabolic-associated
fatty
liver
disease
(MAFLD)
pandemic
has
entered
global
stage.
MAFLD
is
a
chronic
progressive
with
accompanying
metabolic
disorders
such
as
type
2
diabetes
mellitus
and
obesity
which
can
progress
asymptomatically
to
cirrhosis
subsequently
hepatocellular
carcinoma
(HCC),
for
date
there
are
almost
no
approved
pharmacologic
options.
Because
very
complex
etiology
it
also
affects
extrahepatic
organs,
multidisciplinary
approach
required
when
comes
finding
an
effective
safe
active
substance
treatment.
The
optimal
drug
should
diminish
steatosis,
fibrosis
inflammation
in
liver,
winner
authorisation
seems
be
that
significantly
improves
histology.
Saroglitazar
(Lipaglyn
