Mecanismos de lesión en la hepatopatía por depósito de ... 2018/… · Mecanismos de lesión en...
Transcript of Mecanismos de lesión en la hepatopatía por depósito de ... 2018/… · Mecanismos de lesión en...
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