Human hepatic in vitro models reveal distinct anti-NASH potencies of PPAR agonists

Abstract

General rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Livogrit Prevents Methionine-Cystine Deficiency Induced Nonalcoholic Steatohepatitis by Modulation of Steatosis and Oxidative Stress in Human Hepatocyte-Derived Spheroid and in Primary Rat Hepatocytes

“…A significant (5.62 ± 0.78 fold, p < 0.05) upregulation of inflammatory C-X-C motif chemokine 5 (CXCL5) was observed in only MCDM incubated spheroids compared to untreated control. CXCL5 regulates the hepatic recruitment of neutrophils and monocytes during NASH [ 38 ]. Livogrit (30 µg/mL) and pioglitazone (10 µM) treatment normalized (p < 0.05) the expression of this inflammatory cytokine ( Figure 4(d) ).…”

Transcriptomics Reveals Discordant Lipid Metabolism Effects between In Vitro Models Exposed to Elafibranor and Liver Samples of NAFLD Patients after Bariatric Surgery

“…However, due to the complexity of NASH and its human-specificity, NASH-related research has been largely directed towards human-based technologies in recent years [ 22 ]. To that extent, we recently developed a methodology that can be employed to study NASH in vitro and screen for potential anti-NASH compounds [ 6 , 7 ]. In the present study, we confirmed the clinical relevance of the thus-developed in vitro disease models by whole genome-based pathway analysis using four publicly available datasets of patients suffering from NASH.…”

“…This indicates that more performant and predictive preclinical models should be employed during the investigation of novel anti-NASH therapeutics. We recently showed that human hepatic in vitro models, including primary human hepatocytes (PHH), human skin precursor-derived hepatic progenitor cells (hSKP-HPC), and HepaRG and HepG2 cell lines, can model key NASH-specific cellular mechanisms and capture potential anti-NASH properties of novel compounds such as peroxisome proliferator-activated receptor (PPAR) agonists, a drug class that is under clinical evaluation for anti-NASH treatment [ 6 , 7 ]. PPARs have a regulatory role in hepatic lipid metabolism and inflammation and multiple dual- and pan-PPAR agonists, which can supposedly lead to a reduction of hepatic lipids and inflammation, are under investigation, including lanifibranor (a pan-PPAR agonist, phase 3, NCT04849728), saroglitazar (a dual PPAR-α/γ agonist, phase 2, NCT03863574), and elafibranor (a dual PPAR-α/δ agonist, phase 3, NCT02704403) [ 3 ].…”

Flow cytometric quantification of neutral lipids in a human skin stem cell-derived model of NASH

“…These successful applications are a consequence of the fact that hSKPs acquire a strong lipid metabolism upon hepatic differentiation to hSKP-HPC. Furthermore, hSKP-HPC recently showed to mimic the anti-steatotic responses induced by a series of PPAR agonists in a similar way as primary human hepatocytes, being the gold standard for hepatic in vitro modelling, emphasizing the position of hSKP-HPC for modelling NASH in vitro [11] . Considering the restricted availability and fragility of primary human hepatocytes, we optimized a flow cytometric method to quantify the anti-steatotic response induced by potential anti-NASH pharmaceuticals in hSKP-HPC.…”