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