Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid

Ijssennagger, Noortje; Janssen, Aafke W. F.; Milona, Alexandra; Pittol, José M. Ramos; Hollman, Danielle A.A.; Mokrý, Michal; Betzel, Bark; Berends, Frits J.; Janssen, Ignace; Mil, Saskia W.C. van; Kersten, Sander

doi:10.1016/j.jhep.2016.01.016

Cited by 78 publications

(94 citation statements)

References 51 publications

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“…OCA was found in the clinic to raise LDL, a risk not observed in pre-clinical animal studies. Both hPCLS and the lipotoxic system reported transcriptional signatures that may explain the cholesterol endpoints observed in the clinical trials for OCA [26, 35]. Additionally, in the lipotoxic system, OCA treatment induced high secretion of ApoB (the primary apoprotein associated with LDL) and increased intracellular levels of cholesterol, suggesting dysregulation of this pathway, in agreement with what was observed in the clinic [31, 34].…”

Section: Human In Vitro Organotypic Models Of Nafldsupporting

confidence: 66%

“…Diverse approaches have been utilized to combine these different cell types into 3D tissues in order to mimic the architecture found in the intact liver, including layered co-cultures, spheroids, micro-patterned surfaces, human precision cut liver slices (hPCLS), and bioprinting [15–19, 26]. Further, many of these tissues can be cultured within specialized devices (e.g.…”

Section: Human In Vitro Organotypic Models Of Nafldmentioning

confidence: 99%

“…While hPCLS fail to incorporate flow aspects, disease-associated risk factors, and have short time windows before the tissue begins to decline in function, they excel at incorporating the full complement of liver cell types and are freshly isolated from the human liver. Ljssennagger et al used hPCLS to evaluate the farnesoid X receptor (FXR)-agonist, obeticholic acid (OCA, 1 µM for 24 h), which is currently in Phase 3 clinical trials for the treatment of NASH, and reported that gene expression profiling revealed on-target engagement of FXR [26]. Similarly, the lipotoxic system developed by Feaver et al observed several clinically-relevant effects with 0.5-µM OCA treatment, including on-target effects and reductions in steatosis, inflammatory cytokines, fibrotic biomarkers, and triglycerides—all of which were observed in the Phase 2b clinical trial [31, 34, 35].…”

Section: Human In Vitro Organotypic Models Of Nafldmentioning

confidence: 99%

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Translating scientific discovery: the need for preclinical models of nonalcoholic steatohepatitis

et al. 2018

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Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the Western world, affecting about 1/3 of the US general population and remaining as a significant cause of morbidity and mortality. The hallmark of the disease is the excessive accumulation of fat within the liver cells (hepatocytes), which eventually paves the way to cellular stress, injury and apoptosis. NAFLD is strongly associated with components of the metabolic syndrome and is fast emerging as a leading cause of liver transplant in the USA. Based on clinico-pathologic classification, NAFLD may present as isolated lipid collection (steatosis) within the hepatocytes (referred to as non-alcoholic fatty liver; NAFL); or as the more aggressive phenotype (known as non-alcoholic steatohepatitis; NASH). There are currently no regulatory agency-approved medication for NAFLD, despite the enormous work and resources that have gone into the study of this condition. Therefore, there remains a huge unmet need in developing and utilizing pre-clinical models that will recapitulate the disease condition in humans. In line with progress being made in developing appropriate disease models, this review highlights the cutting-edge preclinical in vitro and animal models that try to recapitulate the human disease pathophysiology and/or clinical manifestations.

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Section: Human In Vitro Organotypic Models Of Nafldsupporting

confidence: 66%

Section: Human In Vitro Organotypic Models Of Nafldmentioning

confidence: 99%

Section: Human In Vitro Organotypic Models Of Nafldmentioning

confidence: 99%

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Translating scientific discovery: the need for preclinical models of nonalcoholic steatohepatitis

et al. 2018

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“…However, progressive necrosis of the outer surfaces and rapid loss of differentiated liver function limits their utility for drug exposures beyond the order of hours (Graaf et al 2007; , Neupert et al 2003). For instance, a recent study evaluating OCA in a human PCLS system failed to demonstrate regulation of CYP7A1 and CYP8B1, key metabolic genes that should be suppressed by FXR activation, attributing it to the rapid loss of metabolic gene expression over the 24 hour period of the study (Ijssennagger et al 2016). …”

Section: Introductionmentioning

confidence: 99%

Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system

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Figler

Blackman

et al. 2017

Toxicology in Vitro

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Nonalcoholic steatohepatitis (NASH) is an emerging health crisis with no approved therapies. Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, shows promise in NASH trials. However, the precise mechanisms mediating OCA effects and impact on cholesterol metabolism are not fully understood. We explored the pharmaco-toxicological effects of OCA on pathophysiological pathways in hepatocytes using a previously described perfused organotypic liver system that allows culture in near-physiological insulin/glucose milieus, and exhibits drug responses at clinically-relevant concentrations. Primary hepatocytes experienced 48 -hour exposure to OCA at concentrations approximating therapeutic (0.5μM) and supratherapeutic (10μM) levels. Global transcriptomics by RNAseq was complimented by cellular viability (MTT), CYP activity assays, and secreted FGF19 levels in the media. Dose-dependent, transcriptional effects suggested suppression of bile acid synthesis (↓CYP7A1, ↓CYP27A1) and increased bile efflux (↑ABCB4, ↑ABCB11, ↑OSTA, ↑OSTB). Pleiotropic effects included suppression of TGFβ and IL-6 signaling pathways, and signatures suggestive of HDL suppression (↑SCARB1, ↓ApoAI, ↓LCAT) and LDL elevation (↑ApoB, ↓CYP7A1). OCA exhibited direct FXR-mediated effects with increased FGF19 secretion. Transcriptomics revealed regulation of metabolic, anti-inflammatory, and anti-fibrotic pathways beneficial in NASH, and predicted cholesterol profiles consistent with clinical findings. Follow-up studies under lipotoxic/inflammatory conditions would corroborate these effects in a disease-relevant environment.

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“…It has a role in the development of atherosclerosis, most likely by modulating blood lipid levels 251 . It regulates the hepatic uptake and clearance of HDL particles in a diet-dependent manner 252 . Pctp inhibits thermogenesis in brown adipose tissue 253 .…”

mentioning

confidence: 99%

PCB-associated steatohepatitis and the role of nuclear receptors.

Clair¹

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Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid

Cited by 78 publications

References 51 publications

Translating scientific discovery: the need for preclinical models of nonalcoholic steatohepatitis

Translating scientific discovery: the need for preclinical models of nonalcoholic steatohepatitis

Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system

PCB-associated steatohepatitis and the role of nuclear receptors.

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