Elafibranor restricts lipogenic and inflammatory responses in a human skin stem cell-derived model of NASH. (June 2019)

• Record Type: Journal Article
• Authors: Boeckmans, Joost; Buyl, Karolien; Natale, Alessandra; Vandenbempt, Valerie; Branson, Steven; De Boe, Veerle; Rogiers, Vera; De Kock, Joery; Rodrigues, Robim M.; Vanhaecke, Tamara
• Is Part Of: Pharmacological research. Volume 144(2019)
• Page Start: 377
• Page End: 389
• Publication Date: 2019-06
• Subjects: Non-alcoholic steatohepatitis (NASH) -- Human skin-derived precursors (hSKP) -- Elafibranor -- Stem cells -- Disease modelling -- Peroxisome proliferator-activated receptor (PPAR)-α/δ; Elafibranor (Pubchem CID: 9864881) -- Insulin (Pubchem CID: 16131099) -- Sodium oleate (Pubchem CID: 23665730) -- Palmitic acid (Pubchem CID: 985) -- Glucose (Pubchem CID: 5793); ACADL acyl-CoA dehydrogenase long chain -- ACADM acyl-CoA dehydrogenase medium chain -- ACADSB acyl-CoA dehydrogenase short branched -- ACADVL acyl-CoA dehydrogenase very long chain -- ACC acetyl-CoA carboxylase -- ACOX1 acyl-CoA oxidase 1 -- APOB apolipoprotein B -- ASK1 apoptosis signal-regulating kinase 1 -- ATG5 autophagy related 5 -- B2M β2-macroglobulin -- BSA bovine serum albumin -- CAV1 caveolin 1 -- CCL C-C motif ligand -- CCR C-C chemokine receptor -- CD36 cluster of differentiation 36 -- cDNA copyDNA -- CPT1A carnitine palmitoyltransferase 1A -- CXCL C-X-C motif chemokine ligand -- DAPI 4′, 6-diamidino-2-phenylin-dole -- DGAT diacylglycerol O-acyltransferase -- DMSO dissolved in dimethyl sulfoxide -- ELOVL6 elongation of very long chain fatty acids 6 -- ER endoplasmic reticulum -- FABP1 fatty acid binding protein 1 -- FAS fatty acid synthase -- FATP fatty acid transport protein -- FBP1 fructose-1, 6-bisphosphatase 1 -- hSKP human skin-derived precursor -- hSKP-HPC human skin-derived precursor hepatocyte-like cell -- HSPA5 heat shock protein family A5 -- IL interleukin -- IPA ingenuity pathways analysis -- LC3II light chain 3II -- LPS lipopolysaccharide -- LXRA liver X receptor A -- NAFLD non-alcoholic fatty liver disease -- NASH non-alcoholic steatohepatitis -- NFκB nuclear factor kappa B -- OCA obeticholic acid -- PANX1 pannexin 1 -- PBS phosphate buffered saline -- PC pyruvate carboxylase -- PCK1 phosphoenolpyruvate carboxykinase 1 -- PFA para-formaldehyde -- PHH primary human hepatocytes -- PNPLA3 patatin-like phospholipase domain-containing protein 3 -- PPAR peroxisome proliferator-activated receptor -- RMA robust multiarray analysis -- SCD1 stearoyl-coenzyme A desaturase 1 -- SREBP1C sterol regulatory element-binding protein 1C -- TAC transcriptomics analysis console -- TGF transforming growth factor -- TNF tumor necrosis factor -- TRAF1 tumor necrosis factor receptor-associated factor 1 -- UBC ubiquitin C -- XBP1 X-box binding protein 1; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2019.04.016
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Non-alcoholic steatohepatitis (NASH) is characterized by hepatocellular steatosis with concomitant hepatic inflammation. Despite its pandemic proportions, no anti-NASH drugs have been approved yet. This is partially because drug development is decelerated due to the lack of adequate tools to assess the efficacy of potential new drug candidates. The present study describes the development and application of a new preclinical model for NASH using hepatic cells generated from human skin-derived precursors. Exposure of these cells to lipogenic (insulin, glucose, fatty acids) and pro-inflammatory factors (IL-1β, TNF-α, TGF-β) resulted in a characteristic NASH response, as indicated by intracellular lipid accumulation, modulation of NASH-specific gene expression, increased caspase-3/7 activity and the expression and/or secretion of inflammatory markers, including CCL2, CCL5, CCL7, CCL8, CXCL5, CXCL8, IL1a, IL6 and IL11. The human relevance of the proposed NASH model was verified by transcriptomics analyses that revealed commonly modulated genes and the identification of the same gene classes between the in vitro system and patients suffering from NASH. The application potential of this in vitro model was demonstrated by testing elafibranor, a promising anti-NASH compound currently under clinical phase III trial evaluation. Elafibranor attenuated in vitro key features of NASH, and dramatically lowered lipid load as well as the expression and secretion of inflammatory chemokines, which in vivo are responsible for the recruitment of immune cells. This reduction in inflammatory response was NFκB-mediated. In summary, this human-relevant, in vitro system proved to be a sensitive testing tool for the investigation of novel anti-NASH compounds.