Human-based systems: Mechanistic NASH modelling just around the corner?. (August 2018)

• Record Type: Journal Article
• Authors: Boeckmans, Joost; Natale, Alessandra; Buyl, Karolien; Rogiers, Vera; De Kock, Joery; Vanhaecke, Tamara; Rodrigues, Robim M.
• Is Part Of: Pharmacological research. Volume 134(2018)
• Page Start: 257
• Page End: 267
• Publication Date: 2018-08
• Subjects: Elafibranor (PubChem CID: 9864881) -- Obeticholic acid (PubChem CID: 447715) -- Pioglitazone (PubChem CID: 4829) -- Rosiglitazone (PubChem CID: 77999) -- Fenofibrate (PubChem CID: 3339) -- Serine (PubChem CID: 5951); ACC1 acetyl-coenzyme A carboxylase 1 -- AdipoR adiponectin receptor -- AOP adverse outcome pathway -- AP-1 activator protein 1 -- APOB apolipoprotein B -- ASC adult stem cells -- α-SMA alpha smooth muscle actin -- CCL C-C chemokine ligand -- CCR C-C chemokine receptor -- CD36 cluster of differentiation 36 -- CHOP CCAAT/enhancer-binding protein homologous protein (CHOP) -- ChREBP carbohydrate-responsive element-binding protein -- CK-18 cytokeratin 18 -- COL collagen type -- CPT-1 carnitine palmitoyltransferase 1 -- CYP cytochrome P450 -- DAMPs danger-associated molecular patterns -- ECM extracellular matrix -- ER endoplasmic reticulum -- ESC embryonic stem cells -- FABP fatty acid-binding protein -- FAE fatty acid elongase -- FAS fatty acid synthase -- FATP-2/5 fatty acid transport protein-2/5 -- FFA free fatty acid -- FXR farnesoid X receptor -- GLP-1 glucagon-like peptide-1 -- HDL high-density lipoprotein -- HMG-CoA 3-hydroxy-3-methyl-glutaryl-coenzyme A -- hSKP-HPC human skin-derived precursors-hepatocyte-like cells -- IL interleukin -- iPSC induced pluripotent stem cells -- LPS lipopolysaccharide -- LXR-α liver X receptor α -- MBOAT7 membrane bound O-acyltransferase domain containing 7 -- MPR misfolded protein response -- NAFLD non-alcholic fatty liver disease -- NASH non-alcoholic steatohepatitis -- NF-κB nuclear factor-kappa B -- NLRP3 nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3 -- OCA obeticholic acid -- PAMPs pathogen-associated molecular patterns -- PHH primary human hepatocytes -- PNPLA3 patatin-like phospholipase domain-containing protein 3 -- PPAR peroxisome proliferator-activated receptor -- PUFA polyunsaturated fatty acid -- PXR pregnane X receptor -- ROS reactive oxygen species -- SCD1 stearoyl-coenzyme A desaturase 1 -- SREBP-1c sterol regulatory element-binding protein -- TGF-β transforming growth factor-β -- TLR toll-like receptor -- TM6SF2 transmembrane 6 superfamily 2 -- TNF-α tumor necrosis factor-α -- UPR unfolded protein response -- VLDL very low-density lipoprotein; Non-alcoholic steatophepatitis (NASH) -- Non-alcoholic fatty liver disease (NAFLD) -- Drug targets -- Disease modelling -- Human-based alternative methods; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2018.06.029
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by excessive triglyceride accumulation in the liver accompanied by inflammation, cell stress and apoptosis. It is the tipping point to the life-threatening stages of non-alcoholic fatty liver disease (NAFLD). Despite the high prevalence of NASH, up to five percent of the global population, there are currently no approved drugs to treat this disease. Animal models, mostly based on specific diets and genetic modifications, are often employed in anti-NASH drug development. However, due to interspecies differences and artificial pathogenic conditions, they do not represent the human situation accurately and are inadequate for testing the efficacy and safety of potential new drugs. Human-based in vitro models provide a more legitimate representation of the human NASH pathophysiology and can be used to investigate the dysregulation of cellular functions associated with the disease. Also in silico methodologies and pathway-based approaches using human datasets, may contribute to a more accurate representation of NASH, thereby facilitating the quest for new anti-NASH drugs. In this review, we describe the molecular components of NASH and how human-based tools can contribute to unraveling the pathogenesis of this disease and be used in anti-NASH drug development. We also propose a roadmap for the development and application of human-based approaches for future investigation of NASH.