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Molecular pathways of nonalcoholic fatty liver disease development and progression

  • Fernando Bessone
  • María Valeria Razori
  • Marcelo G. Roma
Review

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a main hepatic manifestation of metabolic syndrome. It represents a wide spectrum of histopathological abnormalities ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis and, eventually, cirrhosis and hepatocellular carcinoma. While hepatic simple steatosis seems to be a rather benign manifestation of hepatic triglyceride accumulation, the buildup of highly toxic free fatty acids associated with insulin resistance-induced massive free fatty acid mobilization from adipose tissue and the increased de novo hepatic fatty acid synthesis from glucose acts as the “first hit” for NAFLD development. NAFLD progression seems to involve the occurrence of “parallel, multiple-hit” injuries, such as oxidative stress-induced mitochondrial dysfunction, endoplasmic reticulum stress, endotoxin-induced, TLR4-dependent release of inflammatory cytokines, and iron overload, among many others. These deleterious factors are responsible for the triggering of a number of signaling cascades leading to inflammation, cell death, and fibrosis, the hallmarks of NASH. This review is aimed at integrating the overwhelming progress made in the characterization of the physiopathological mechanisms of NAFLD at a molecular level, to better understand the factor influencing the initiation and progression of the disease.

Keywords

Nonalcoholic fatty liver disease Nonalcoholic steatohepatitis Lipotoxicity Oxidative stress Liver fibrosis Hepatocellular death 

Abbreviations

ACC2

Acetyl-CoA carboxylase 2

AhR

Aryl hydrocarbon receptor

AIF

Apoptosis-inducing factor

AMPK

AMP-activated protein kinase

AP-1

Adaptor protein-1

Apaf-1

Apoptotic protease-activating factor 1

Apo

Apolipoprotein

ASC

Apoptotic speck-like protein containing caspase-1 activation and recruitment domain

ATG13

Autophagy-related protein 13

Bad

Bcl-2 antagonist of cell death

Bak

Bcl-2-associated X killer

Bax

Bcl-2-associated X protein

Bcl-2

B cell lymphoma-2

Bcl-xL

B-cell lymphoma-extra large

BH3

Bcl-2 homology-3

Bim

BCL-2-interacting mediator of cell death

CaMKII

Calcium- and calmodulin-dependent protein kinase II

CAT

Carnitine acetyl transferase

CHOP

CCAAT/enhancer-binding protein homologous protein

ChREBP

Carbohydrate response element binding protein

CoA

Coenzyme A

CPT1

Carnitine palmitoyltransferase 1

CTGF

Connective tissue growth factor

CYP2E1

Cytochrome P450 family 2 subfamily E member 1

DAMP

Danger-associated molecular pattern

DIABLO

Direct inhibitor of apoptosis protein binding protein with low pi

DISC

Death-inducing signaling complex

ER

Endoplasmic reticulum

Erk

Ras/extracellular signal-regulated kinase

FasL

Fas ligand

FIP200

FAK family-interacting protein of 200 kDa

FoxO1

Forkhead box protein O1

FP-1

Ferroportin-1

FFA

Free fatty acid

G6P

Glucose-6 phosphatase

GK

Glycogen kinase

GSK

Glycogen synthase kinase

HCC

Hepatocellular carcinoma

Hh

Hedgehog

HJV

Hemojuvelin

HSC

Hepatic stellate cell

IAP

Inhibitors of apoptosis protein

IGF2BP2-2

Insulin-like growth factor 2 (IGF2) mRNA-binding protein-2

I-κB

Inhibitor of κB

IKK

IκB kinase

IL

Interleukin

InsP3R1

Inositol 1,4,5-triphosphate receptor 1

IR

Insulin resistance

IRS1/2

Insulin receptor substrates 1/2

JAK

Janus activated kinase

JNK

c-Jun N-terminal kinase

LPS

Lipopolysaccharide

LXR

Liver X receptor

L-PK

Liver-type pyruvate kinase

Mcl-1

Myeloid cell leukemia sequence-1

MCP-1

Monocyte chemoattractant protein 1

MEK1

Mitogen activated protein kinase 1

MMP

Matrix metalloproteinase

MPTP

Mitochondrial permeability transition pore

mTOR

Mammalian target of rapamycin

MyD88

Myeloid differentiation primary response 88

NAFLD

Nonalcoholic fatty liver disease

NALP3

NACHT, LRR and PYD domains-containing protein 3

NASH

Nonalcoholic steatohepatitis

NLR

NOD-like receptor

NOX4

NADPH oxidase 4

NF-κB

Nuclear factor-κB

PCK1

Phosphoenolpyruvate carboxykinase

OS

Oxidative stress

PUMA

p53 upregulated modulator of apoptosis

PDGF

Platelet-derived growth factor

PEMT

Phosphatidylethanolamine N-methyltransferase

PI3K

Phosphoinositide 3-kinase

PKCθ

Protein kinase C-θ

PP2A

Protein phosphatase 2A

PPAR-α

Peroxisome proliferator-activated receptor-α

PTPRO

Protein tyrosine phosphatase receptor type O

ROS

Radical oxygen species

SAMe

S-adenosylmethionine

SCAP

SREBP-cleavage activating protein

SMAC

Second mitochondria-derived activator of caspases

SOCS

Suppressor of cytokine signaling

SREBP-1c

Sterol regulatory binding protein-1c

STAT3

Signal transducer and activator of transcription 3

TAK1

TGF-β activated kinase-1

TG

Triglyceride

TGF-β

Transforming growth factor-β

TIMP-1

Tissue inhibitor of metalloproteinase-1

TLR4

Toll-like receptor 4

TNF-α

Tumor necrosis factor-α

Ulk1/2

Unc-51 like autophagy activating kinase 1/2

VLDL

Very low density lipoprotein

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© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y HepatologíaUniversidad Nacional de RosarioRosarioArgentina
  2. 2.Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y FarmacéuticasUniversidad Nacional de RosarioRosarioArgentina

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