Mecanismos de lesión en la hepatopatía por depósito de ... 2018/… · Mecanismos de lesión en la hepatopatía por depósito de grasa Prof. Manuel Romero Gómez. Digestive Diseases.

Mecanismos de lesión en la hepatopatía por depósito de grasa

Prof. Manuel Romero Gómez. Digestive Diseases. HUVRocío, SeLiver

Group IBIS, Universidad de Sevilla, Sevilla.

ASPECTOS DIAGNÓSTICOS Y PATOGÉNICOS EN HEPATOLOGÍA

XVII JORNADAS DE AVANCES EN HEPATOLOGÍA

NASH is currently the second leading cause of liver transplant worldwide, and the number of receptors has tripled since 2004.

NAFLD patients have an increased risk of mortality, related to both liver and cardiovascular diseases, with hepatic fibrosis being the best predictor of mortality.

Simple esteatosis NASH Cirrhosis

NASH

Hepatocellular carcinoma

Descompensations

Transplant 15-20% 10-20%

NAFLD overview

Zezos et al, World J Gastroenterol 2014; Ekstedt et al, Hepatology 2015; Wong et al, Gastroenterology 2015

INDIVIDUAL PREDISPOSITION

KICK-OFF DISEASE

PHENOTYPE

Resolution Stabilization Progression

SIMPLE STEATOSIS STEATOHEPATITIS LIVER FIBROSIS CIRRHOSIS HCC

Buzzetti et al, Metabolism 2016; Ratziu et al, J Hepatol 2015

Prevalence 6-33%

Background NAFLD overview

Apoptosis

Senescence Necrosis

IR Inflamma-

tion Oxidative

Stress

FFA Uptake

DNL

Metabolomic

Proteomic Lipidomic

Transcriptomic

RNA ncRNA

Genomics

Metagenomics

NAFLD pathogenesis

Fatty acid released from adipose tissue

into the blood

Dietary fat

Chylomicron triglyceride

Adipose tissue

Liver free fatty acids

Oxidative disposal

Dietary sugars

Fructose Glucose

Acetil CoA

Fatty acids made in the liver

de novo lipogenesis

Triglycerides

VLDL Hypertrigliceridemia

Lipotoxic lipids

Hepatocellular injury

Inflammation/repair

NASH

Fibrosis

HCC

Genetic and epigenetic modifiers

Adapted from Neuschwander-Tetri, BMC Medicine 2017 Cohen JC et al. Science 332, 1519 (2011)

HEPATOLOGY, Vol. 52, No. 5, 2010

NASH: Del doble impacto al impacto múltiple

Fat-liver axis

Gut-liver axis

Epitelio Intestinal

Microbiota

MALT

Inducción de moco Inducción de péptidos antimicrobianos Producción y transporte de anticuerpos IgA

Composición de la Microbiota

Inducción del MALT Regulación del SI periférico Modulación de la actividad del SI -Tolerancia -Inflamación Fisiológica

Situación Fisiológica

MALT: Tejido linfoide asociado a las mucosas

Luz Intestinal

Lámina Propia

Estado Patológico

Th17

Th1

IL-6, IL-1β, TGFβ, IL-23,

IL-12

Treg

Disbiosis Interacción desregulada con PRRs en

las regiones laterales de los enterocitos

Patógenos que atraviesan la barrera epitelial

Destrucción del epitelio Intestinal Enfermedad Inflamatoria Intestinal

Patologías Inflamatorias Sistémicas

Migración órganos linfoides periféricos

Microbiome: From study to therapeutic target

Chassaing B et al. Hepatology 2014 Abu-Shanab, A. & Quigley, E. M. M. Nat. Rev. Gastroenterol Hepatol 2010;7, 691–701 (2010)

Intestinal barrier

Vascular barrier

Zhu et al. Hepatology 2013;57:601-609

Bacteroides Prevotella

Enterotipo 1 22%-39% 0%-1%

Enterotipo 2 2%-17% 6%-36% NASH Enterotipo 3 3%-16% 0%-8%

Controles Obesos NASH

Varones 10/16 13/25 12/22

Edad 14,4+1,8 12,7+3,2 13,6+3,5

IMC 20,4+0,1 33,4+0,3 34+04

ALT ND 27+0,6 67+2

N=63 [Control (n=16); obesos (n=25), NASH (n=22)]

Alcohol & NASH

Conexión entre microbioma y producción endógena de alcohol en NASH

N=63 [Control (n=16); obesos (n=25), NASH (n=22)]

Zhu et al. Hepatology 2013;57:601-609

0

2

4

6

8

10

Actinobacteria Proteobacteria

HC Ob NASH

0

20

40

60

80

100

Bacteroidetes Fimicutes

HC Ob NASH

(*) Proteobacterias: Enterobacteriaceae & Escherichia

(*)

La concentración de alcohol en sangre periférica se midió con un kit colorimétrico de etanol BioVision (Milpitas, CA) que determina qué cantidad de alcohol ha sido oxidado por la enzima alcohol oxidasa.

Bacterias Gram- promueven resistencia a la insulina, incrementan la producción endógena de alcohol e inducen deficiencia en colina, por efecto de la cubierta polisacárida de estas bacterias.

Liver biopsy: Histological diagnosis of steatohepatitis

SAF Score Steatosis Ballooning Lobular Inflammation

0 <5% No No

1 5%-33% Yes 1 foci

2 33%-66% prominent >2 foci

3 >66%

Fat droplets

• VLDL synthesis

• Surface lipoproteins

• Fatty acid disposal

• Interaction with cytoskeleton

Welte MA, Curr Biol 2005;15:1266-75

Gorden et al. J Lipid Res 2015; 56:722

Biomarkers of NAFLD progression: a lipidomic approach to an epidemic.

1. Glycerophospholipids 2. Cardiolipin, coenzyme Q, and

dolichol. 3. FAs and eicosanoids. 4. Sterols and oxysterols. 5. Neutral lipids: Cholesteryl esters

(CEs), TAGs, and DAGs 6. Sphingolipids.

LIVER 186 Lipid Species

with p under critical value

of false detection rate

PLASMA 132 Lipid Species with p under critical value

of false detection rate

48 Lipid

Species

Puri P et al. Hepatology 2009;50:1827-38.

INFLAMMATION

LIPOGENESIS

OXIDATIVE STRESS

Circulating Lipidome Model for NAFLD Pathophysiology

LOX activation

Oxidation of lipids

De novo lipogenesis

Peroxisomal dysfunction

Estrés oxidativo y esteatohepatitis

1. Estrés oxidativo es crucial en la patogenia de NASH

2. Metabolismo del alcohol y ácidos grasos vía CYP2E1

3. Activación CYP2E1 (x RI) progresión de NASH

Leung et al. J Hepatol 2013;58:395-398 Angulo P. N Eng J Med 2002;346:1221

RI - Esteatosis

Estrés oxidativo

Ballooning

Ballooned cells: lack normal keratin staining & correlates to fibrosis

H & E staining ‘Keratin empty’ on K 8/18 staining

Superoxide spark Sources of super oxide (free radical):

Peroxisomes

Mitochondria (electron transport chain)

Endoplasmic reticulum

Organelle permeability

Cytoskeletal injury

PAT / APO B / VLDL Fat droplet metabolism

Oxidative injury

‘Multi-organelle’ failure

Impaired Fat Droplet Metabolism

Impaired Fatty Acid Disposal: Lipotoxicity

Ballooning, Fibrosis and necro-apoptosis

Too sick to live Too weak to die Multiorganelle failure

Kakisaka J Hepatol 2012;57:844 Rangwala, Diehl J Pathol 2011

The Undead Ballooned Cell

Fibrosis depends on Stellate cell activation governed by macrophages

Activated stellate cell: alpha smooth muscle staining with extention into Space of Disse

Stellate cell activity governed by macrophages

Washington et al Hum Pathol 2000

NAFLD: inflammation and fibrosis

Genetics of NASH and NAFLD

• PNPLA3: adiponutrin/patatin-like phospholipase-3 – rs738409 C→G, encoding the I148M – CG and GG have increased steatosis and

fibrosis – Interaction with fat droplet metabolism – VLDL synthesis, stellate cell release of retinol

• TM6SF2: transmembrane 6 superfamily member 2

– Expressed in liver and intestines – Localizes to ER and Golgi – Alters lipid droplet and lipoprotein composition – Associated with disease severity

Valenti 2010, Pirazzi 2012 and 2014, Mahdessian 2014, Kozlitina 2014, Liu 2014

P=5.9 X 10-10 5.4 x 10-6

Vilar et al. Gastroenterology 2018 (In Press)

El bueno, el feo y el malo de Sergio Leone en NAFLD/NASH

ALCOHOL

FAT FIBROSIS

Adapted from Johnson et al. Exercise and Liver: Implications for therapy in fatty liver disorders, Semin Liv Dis 2012

Weight loss

Exercise

Physical activity

Diet

Expected effect of lifestyle modifications

PPAR α/δ

PIOGLITAZONE

OBETICHOLIC ACID

ARAMCHOL

FXR

EMRICASAN

VITAMIN E PENTOXIFILINE

CENICRIVIROC

SIMTUZUMAB ELAFIBRANOR

GLP-1

LIRAGLUTIDE SEMAGLUTIDE

TNF-α TGFB1

antioxidante

Lipogenesis de novo FFA uptake Metabolic

stress Inflammation Oxidative stress Apoptosis Fibrosis

Caspase Lipasa intestinal

SCD LOXL2

CCR2/CCR5

ORLISTAT

PPARγ

ASK1

SELONSERTIB

FGF21

BMS-986036

FGF19

NMG-282

LJN452

IVA337

PPARα/δ/γ

ND-630

ACC

@SeLiver_group

Thank You

Courtesy- Dr. David Kleiner

FGFR4

OCA

FGF19

FXR

SREBP-1 VLDL FFA

CYP7A1

Cholesterol Bile acids

NFkB

TNFα INF ɣ

INOS

COX2 MCP1

IL1β IL6

PEPCK

Neoglucogenesis

Lipid and glucose Metabolism

Triglycerides synthesis

VLDL production

Bile acids production

Neoglucogenesis in the liver

Inflammation

NFkB

TNFα, INF ɣ, IL1, IL17

COX2

Triglycerides

Hepatocyte

Ampuero et al. Gastroenterol Hepatol 2017

Dual PPARa/d Agonists ELAFIBRANOR PPARα

• Fatty acid oxidation • TG lowering • HDL raising • Antiinflammatory

PPARδ

• Lipoprotein metabolism • Glucose homeostasis • Energy metabolism • Antiinflammatory

Absence of safety concern, Absence of PPAR deleterious effect Anti-inflammatory properties

Favorable effects on plasma lipids Improvement of markers of liver dysfunction

Improvement of glucose homeostasis & insulin sensitivity

GFT-505

Dual anti-obesity and anti-NASH effects of GLP-1 agonists

Van Gaal L. European Congress on Obesity (ECO) 2015. Abstract 0S2.1.

N= 52 (17 T2DM & 27 F3/F4) 45 paired liver biopsies

39%

9%

0 10 20 30 40 50

Liraglutide

Placebo

NASHRES

P<0.04; O.R. 6.43 (1.2-34.4)

Armstrong MJ et al. Lancet 2016

Selonsertib

ASK1

ASK1

p38 JNK

P

P

↑Activation ↑Collagen production

↑Cytokines ↑Apoptosis ↑Insulin resistance ↑Lipogenesis

Selonsertib: ASK1 inhibitor mechanism of action

Adapted from Schuster, Feldstein Nat Rev Gastro Hepatol 2017 INT/0165/2017g