Precision-cut liver slices in culture as a tool to assess the physiological involvement of Kupffer cells in hepatic metabolism

Neyrinck, Audrey M.; Gómez, Cristina

doi:10.1186/1476-5926-2-s1-s45

Cited by 16 publications

(8 citation statements)

References 11 publications

(15 reference statements)

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“…Last, indole up-regulated the Ptgs2 gene expression in PCLS, potentially leading to an increased production of prostaglandin E 2 that has immunoregulatory properties in the liver and is protective against liver injury (5, 42, 43). These effects were lost in PCLS prepared from CL-treated mice, consistent with the major role of KC in the expression of PTGS2 in the liver (44). …”

Section: Discussionsupporting

confidence: 66%

The gut microbiota metabolite indole alleviates liver inflammation in mice

et al. 2018

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The gut microbiota regulates key hepatic functions, notably through the production of bacterial metabolites that are transported via the portal circulation. We evaluated the effects of metabolites produced by the gut microbiota from aromatic amino acids (phenylacetate, benzoate, p-cresol, and indole) on liver inflammation induced by bacterial endotoxin. Precision-cut liver slices prepared from control mice, Kupffer cell (KC)-depleted mice, and obese mice (ob/ob) were treated with or without LPS and bacterial metabolites. We observed beneficial effects of indole that dose-dependently reduced the LPS-induced up-regulation of proinflammatory mediators at both mRNA and protein levels in precision-cut liver slices prepared from control or ob/ob mice. KC depletion partly prevented the antiinflammatory effects of indole, notably through a reduction of nucleotide-binding domain and leucine-rich repeat containing (NLR) family pyrin domain-containing 3 (NLRP3) pathway activation. In vivo, the oral administration of indole before an LPS injection reduced the expression of key proteins of the NF-κB pathway and downstream proinflammatory gene up-regulation. Indole also prevented LPS-induced alterations of cholesterol metabolism through a transcriptional regulation associated with increased 4β-hydroxycholesterol hepatic levels. In summary, indole appears as a bacterial metabolite produced from tryptophan that is able to counteract the detrimental effects of LPS in the liver. Indole could be a new target to develop innovative strategies to decrease hepatic inflammation.—Beaumont, M., Neyrinck, A. M., Olivares, M., Rodriguez, J., de Rocca Serra, A., Roumain, M., Bindels, L. B., Cani, P. D., Evenepoel, P., Muccioli, G. G., Demoulin, J.-B., Delzenne, N. M. The gut microbiota metabolite indole alleviates liver inflammation in mice.

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Section: Discussionsupporting

confidence: 66%

The gut microbiota metabolite indole alleviates liver inflammation in mice

et al. 2018

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“…Still the majority of studies carry out drug-induced liver injury (DILI) experiments and can only evaluate the slices the first 72 h. The focus of most read-outs relies on hepatocyte functionality, survival and metabolism while few studies focus on HSCs, Kupffer cells or endothelial cells. As the focus of PCLS research shifts more towards using the model to study chronic liver diseases, more researchers have started to investigate these sinusoidal cell types as well [110][111][112][113][114][115][116].…”

Section: Discussionmentioning

confidence: 99%

Best Practices and Progress in Precision-Cut Liver Slice Cultures

Dewyse

Reynaert

Grunsven

2021

IJMS

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Thirty-five years ago, precision-cut liver slices (PCLS) were described as a promising tool and were expected to become the standard in vitro model to study liver disease as they tick off all characteristics of a good in vitro model. In contrast to most in vitro models, PCLS retain the complex 3D liver structures found in vivo, including cell–cell and cell–matrix interactions, and therefore should constitute the most reliable tool to model and to investigate pathways underlying chronic liver disease in vitro. Nevertheless, the biggest disadvantage of the model is the initiation of a procedure-induced fibrotic response. In this review, we describe the parameters and potential of PCLS cultures and discuss whether the initially described limitations and pitfalls have been overcome. We summarize the latest advances in PCLS research and critically evaluate PCLS use and progress since its invention in 1985.

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“…Precision-cut liver slices (PCLS) were prepared as previously described [32, 33]. PCLS were incubated without (control medium) or with vildagliptin (0.6 mg/ml) in oxygenated and supplemented Waymouth’s medium for 4 h at 37°C under agitation.…”

Section: Methodsmentioning

confidence: 99%

“…After 1 week of acclimatisation, mice in experiment 2 were anesthetised with ketamine (100 mg/kg body weight) (Nimatek; Eurovet, Bladel, Netherlands) and xylazine (100 mg/kg body weight) (Rompun; Bayer, Leverkusen, Germany). Precision-cut liver slices (PCLS) were prepared as previously described [ 32 , 33 ]. PCLS were incubated without (control medium) or with vildagliptin (0.6 mg/ml) in oxygenated and supplemented Waymouth’s medium for 4 h at 37°C under agitation.…”

Section: Methodsmentioning

confidence: 99%

The DPP-4 inhibitor vildagliptin impacts the gut microbiota and prevents disruption of intestinal homeostasis induced by a Western diet in mice

et al. 2018

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Aims/hypothesisDipeptidyl peptidase 4 (DPP-4) inhibitors are agents designed to increase the half-life of incretins. Although they are administered orally, little is known about their effects on the gut microbiota and functions, despite the fact that some bacteria present in the gut microbiota exhibit DPP-4-like activity. Our objective was to study the impact of the DPP-4 inhibitor vildagliptin on gut functions and the intestinal ecosystem in a murine model of obesity induced by a Western diet (WD).MethodsTwenty seven male C57BL/6J mice were randomised to receive a control diet, a WD (45% kJ from fat and 17% kJ from sucrose) or a WD + vildagliptin (0.6 mg/ml in drinking water) for 8 weeks.ResultsVildagliptin significantly reduced DPP-4 activity in the caecal content and faeces. Vildagliptin impacted on the composition of the gut microbiota and its metabolic activity. It mainly decreased Oscillibacter spp. (a direct effect independent of DPP-4 activity was shown on cultured O. valericigenes), increased Lactobacillus spp. and propionate, and reduced the ligands of Toll-like receptors 2 and 4. Vildagliptin protected against the reductions in crypt depth and ileal expression of antimicrobial peptides induced by the WD. In the liver, the expression of immune cell populations (Cd3g and Cd11c [also known as Itgax]) and cytokines was decreased in the WD + vildagliptin-fed mice compared with the WD-fed group. Ex vivo exposure of precision-cut liver slices to vildagliptin showed that this response was not related to a direct effect of the drug on the liver tissue.Conclusions/interpretationOur study is the first to consider the DPP-4-like activity of the gut microbiota as a target of DPP-4 inhibition. We propose that vildagliptin exerts beneficial effects at the intestinal level in association with modulation of gut microbiota, with consequences for hepatic immunity. If relevant in humans, this could open new therapeutic uses of DPP-4 inhibition to tackle gut dysfunctions in different pathophysiological contexts.Data availabilityThe sequences used for analysis can be found in the MG-RAST database under the project name MYNEWGUT3.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4647-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Precision-cut liver slices in culture as a tool to assess the physiological involvement of Kupffer cells in hepatic metabolism

Cited by 16 publications

References 11 publications

The gut microbiota metabolite indole alleviates liver inflammation in mice

The gut microbiota metabolite indole alleviates liver inflammation in mice

Best Practices and Progress in Precision-Cut Liver Slice Cultures

The DPP-4 inhibitor vildagliptin impacts the gut microbiota and prevents disruption of intestinal homeostasis induced by a Western diet in mice

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