ppar biology beyond thiazolidinediones and novel ...cholesterol homeostasis, fatty acid metabolism...
TRANSCRIPT
Univ. Lille - EGID; INSERM U1011; Institut Pasteur de Lille; CHU Lille
Lille, France
Bart Staels
PPAR biology beyond thiazolidinediones
and novel applications for NASH
Focus on PPARa and PPARd
Genfit SA, Co-founder, President of Scientific Advisory Board
Faculty Disclosure Information Elements
Day
Glycolysis
Lipogenesis
Fedinsulin
NightFastedglucagon
FA oxidation
GluconeogenesisMetabolic
Flexibility
Pawlak et al. J.Hepatol. 2014
Maintenance of «Metabolic Flexibility»
To Avoid Metabolic Disorders
Day
Glycolysis
Lipogenesis
Fedinsulin
NightFastedglucagon
FA oxidation
Gluconeogenesis PPARa/d
Pawlak et al. J.Hepatol. 2014
PPARa and d Control «Metabolic Flexibility»
To Avoid Metabolic Disorders
Overfeeding saturated fat is more harmful for
the human liver than unsaturated fat or simple sugars
Luukkonen PK et al. Diab Care 2018;41:1732
Overfeeding saturated fat induced insulin resistance, endotoxemia
and plasma ceramides
Haas, Vonghia, Mogilenko et al. Nature Metab. 2019;1:604-14
Immune cells linking NAFLD and CVD
Mogilenko et al. Cell 2019 7
Glycolysis
Cytokine
production
(IL23, IL6, ...)
T cell
activation
Bone Marrow-derived DC
Metabolic
Reprogramming
Free
Fatty
Acids
Toll-LikeReceptor(TLR)
↓ Glycolysis
↑ Oxidative Stress
↑ Unfolded Protein Response
↑ Lipogenesis
Metabolism Immunity
The metabolic environment alters the cytokine
response of dendritic cells
Carbohydrates DNL
Saturated
fatty acidsPalmitate
Diet Liver
Metabolic
perturbation Unsaturated
fatty acids
PPARd
PPARd Modifies Fat Quality to Improve Metabolism
Luukkonen Diab Care 2018;41:1732; Chavez & Summers Cell Metab 2012;15:585
PPARa Programs The Metabolic Adaptation
in the Fed-Fasted Transition Periods
Pawlak et al. J.Hepatol. 2014
Elafibranor 80mg/d Elafibranor 80mg/d
Placebo Placebo
0 4 8 18 22 2414-2 weeks
V1 V6V5V2 V4V3 V7 V8
Wash-out
PPARa/d activation improves insulin sensitivity(two-step hyperinsulinemic-euglycemic clamp in pre-diabetic individuals)
**
1st step(0.2 UI/kg/min)
EGP
**
*
GIR
Cariou B. et al.
Diab.Care 2013
Histological feature,Term Enrichment (up/down)
SteatosisCholesterol homeostasis, fatty acid metabolism Steroid biosynthetic process, xenobiotic metabolism
Response to cytokines
Monocarboxylic acid metabolic process
Lobular inflammation and ballooning Inflammatory response, IL6 and PDGFR signaling pathwaysRegulation of transmembrane transport, bile secretion
Response to cytokines, epithelial-mesenchymal transition
FibrosisEpithelial-mesenchymal transition,wound healing Methionine metabolic process, organo-nitrogen compound metabolic process
NAFLNASH
-FIBROSISNASH
+FIBROSIS
Gene Counts
(up/down) 34/23 6/5 86/25 26/5 75/23
Francque S. et al. J.Hepatol. 2015Lefebvre P. et al.JCI Insight 2017
Hepatic PPARα Expression and Signaling Reversibly
Decrease Upon NAFLD Disease Progression
PPARa
Cas12
IRE1
PERK
Nucleus
ATF6
uXBP1
eIF2α
P
BiP
Grp94ORP150
sXBP1
ATF4
SP2
SP1
ATF6
Proteintranslation
ATF6
Apoptosis
Grp170
Golgi
Endoplasmic reticulum
ATF4sXBP1
Cytoplasm
Misfolded Proteins
BiP
BiP
Folding (bip)ERAD (edem)Anti-oxidant (gst)Feedback (gadd34)Apoptosis (chop)
Golgi apparatus
C. Hetz, Nat. Rev. Mol. Cell Biol.,
2012
The Unfolded Protein Response (UPR)
is activated in NASH
Adapted from Boulinguiez et al. BBA Lipids 2017
Dpt
*
*lo
g2(r
ela
tive
ge
ne
exp
ressio
n)
Fibrosis stage0
0.253
0.5
1
2
4
*
*
PPARa
1 2
PPARb
PPARg
Cirrhosis increases the risk for sepsis:
Is there a role for PPARa in the response to sepsis?
Lefebvre P. et al. JCI Insight
hep
WT
a
PPAR
hepKO
a
PPAR
KO
a
PPAR
0
1
2
3
4 BeforeAfter
***
§§§
§§§§
Ke
ton
e b
od
ies
(m
mo
l/L
)
B
Ketone bodies
Hepatocyte PPARa-deficiency decreases
survival upon bacterial infection
Paumelle R. et al. J.Hepatol.2019Collaboration with H.Guillou, Toulouse
Survival curve
0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 0
0
2 0
4 0
6 0
8 0
1 0 0
P p a rah e p K O
P p a rah e p W T
P p a ra K O
***
*
h rs p o s t-in fe c t io n
Pe
rc
en
t s
urv
iva
l
Log-rank (Mantel-Cox) test: *** p<0.01, * p<0.005
Hepatocyte ketogenesis protects against NASH
through paracrine modulation of macrophage function
Puchalska P et al. Cell Metab 2019;29:383; Torok NJ Hepatology. 2019 doi: 10.1002/hep.30777
PPARa/d activation with elafibranor prevents
adenoma and HCC development
(CD/FF diet-induced NASH model)
CD/FF CD/FF ElafibranorMacroscopic nodules
Walczak R et al. AASLD 2018; poster presentation
Tumor occurence
Benign HCC
Walczak R et al. AASLD 2018; poster presentation
PPARa/d activation with elafibranor prevents
adenoma and HCC development
(CD/FF diet-induced NASH model)
PPARa/d activation and ACC inhibition synergize to normalisesteatosis in a NASH model
(studies with low doses of elafibranor and GS-0976)
Hepatic TG content Plasma ketone bodies
Legry V et al. AASLD 2018; poster presentation
PPARa/d activation synergizes with anti-fibrotic therapies to attenuate fibrosis in a NASH model
(studies with elafibranor and nitazoxanide)
Hepatic collagen
Bélanger C et al. EASL-NASH Summit 2019; poster presentation
Co
llag
en
pro
po
rtio
nala
rea
(%
)
mg
co
llag
en
/g li
ve
r
Hepatic fibrosis area
CSAA Ctrl ELA NTZ ELA+NTZ
CDAA/c
CSAA Ctrl ELA NTZ ELA+NTZ
CDAA/c
AcknowledgmentsUniv. Lille, Inserm U1011Institut Pasteur de Lille, FE. Baugé
H. Dehondt
Y. Deleye
B. Derudas
J. Eeckhoute
C. Gheeraert
J. Haas
N. Hennuyer
S. Lestavel
D. Mogilenko
R. Paumelle
B. Pourcet
A. Tailleux
D. Dombrowicz
P. Lefebvre
Genfit, Lille, F R. Hanf
DW.Hum
S.Megnien
B.Noel
A.Roudot
R.Walczak
ClinicalInvestigators
A.Sanyal
SA.Harrison
B.Cariou
M.Laville
V.Ratziu
H.Vidal
Antwerp Univ Hospital,BelgiumL.Vonghia
A.Verrijken
L.Van Gaal
S.Francque
UMR1331 & 1048, ToulouseH.Guillou
P.Gourdy
A.Montagner
Kowa Co, Japan T. Takizawa
Y. Yamazaki
S. Tanabe
KUL, BelgiumG.Van Den Berghe
L.Langouche