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Molecular pathways of nonalcoholic fatty liver disease development and progression

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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.

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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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  1. Fernando Bessone and María Valeria Razori have contributed equally to this work.

Authors and Affiliations

  1. Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina

    Fernando Bessone

  2. Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Argentina

    María Valeria Razori & Marcelo G. Roma

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Bessone, F., Razori, M.V. & Roma, M.G. Molecular pathways of nonalcoholic fatty liver disease development and progression. Cell. Mol. Life Sci. 76, 99–128 (2019). https://doi.org/10.1007/s00018-018-2947-0

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