Cellular and Molecular Life Sciences

, Volume 76, Issue 1, pp 99–128 | Cite as

Molecular pathways of nonalcoholic fatty liver disease development and progression

  • Fernando Bessone
  • María Valeria Razori
  • Marcelo G. RomaEmail author


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.


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



Acetyl-CoA carboxylase 2


Aryl hydrocarbon receptor


Apoptosis-inducing factor


AMP-activated protein kinase


Adaptor protein-1


Apoptotic protease-activating factor 1




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


Autophagy-related protein 13


Bcl-2 antagonist of cell death


Bcl-2-associated X killer


Bcl-2-associated X protein


B cell lymphoma-2


B-cell lymphoma-extra large


Bcl-2 homology-3


BCL-2-interacting mediator of cell death


Calcium- and calmodulin-dependent protein kinase II


Carnitine acetyl transferase


CCAAT/enhancer-binding protein homologous protein


Carbohydrate response element binding protein


Coenzyme A


Carnitine palmitoyltransferase 1


Connective tissue growth factor


Cytochrome P450 family 2 subfamily E member 1


Danger-associated molecular pattern


Direct inhibitor of apoptosis protein binding protein with low pi


Death-inducing signaling complex


Endoplasmic reticulum


Ras/extracellular signal-regulated kinase


Fas ligand


FAK family-interacting protein of 200 kDa


Forkhead box protein O1




Free fatty acid


Glucose-6 phosphatase


Glycogen kinase


Glycogen synthase kinase


Hepatocellular carcinoma






Hepatic stellate cell


Inhibitors of apoptosis protein


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


Inhibitor of κB


IκB kinase




Inositol 1,4,5-triphosphate receptor 1


Insulin resistance


Insulin receptor substrates 1/2


Janus activated kinase


c-Jun N-terminal kinase




Liver X receptor


Liver-type pyruvate kinase


Myeloid cell leukemia sequence-1


Monocyte chemoattractant protein 1


Mitogen activated protein kinase 1


Matrix metalloproteinase


Mitochondrial permeability transition pore


Mammalian target of rapamycin


Myeloid differentiation primary response 88


Nonalcoholic fatty liver disease


NACHT, LRR and PYD domains-containing protein 3


Nonalcoholic steatohepatitis


NOD-like receptor


NADPH oxidase 4


Nuclear factor-κB


Phosphoenolpyruvate carboxykinase


Oxidative stress


p53 upregulated modulator of apoptosis


Platelet-derived growth factor


Phosphatidylethanolamine N-methyltransferase


Phosphoinositide 3-kinase


Protein kinase C-θ


Protein phosphatase 2A


Peroxisome proliferator-activated receptor-α


Protein tyrosine phosphatase receptor type O


Radical oxygen species




SREBP-cleavage activating protein


Second mitochondria-derived activator of caspases


Suppressor of cytokine signaling


Sterol regulatory binding protein-1c


Signal transducer and activator of transcription 3


TGF-β activated kinase-1




Transforming growth factor-β


Tissue inhibitor of metalloproteinase-1


Toll-like receptor 4


Tumor necrosis factor-α


Unc-51 like autophagy activating kinase 1/2


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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