Bile salts regulate CYP7A1 expression and elicit a fibrotic response and abnormal lipid production in 3D liver microtissues

Messner, Catherine Jane; Mauch, Linda; Suter‐Dick, Laura

doi:10.1016/j.tiv.2019.06.002

Cited by 13 publications

(10 citation statements)

References 67 publications

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“…The results from this experiment show that BAs exert a temporal cytotoxicity that is not mediated via mitochondrial dysfunction. A recent publication in HepaRG cells found that bile salt treatment caused a decrease in the expression and release of albumin and a reduction in the biliary excretory capacity as seen in this study (Messner et al, 2019). Biomarker analysis revealed that levels of the hepatocyte-specific marker miR-122 were elevated thus suggesting overall hepatocyte injury (Messner et al, 2019).…”

Section: Resultssupporting

confidence: 78%

“…A recent publication in HepaRG cells found that bile salt treatment caused a decrease in the expression and release of albumin and a reduction in the biliary excretory capacity as seen in this study (Messner et al, 2019). Biomarker analysis revealed that levels of the hepatocyte-specific marker miR-122 were elevated thus suggesting overall hepatocyte injury (Messner et al, 2019). Other proposed mechanisms of toxicity include ROS generation, endoplasmic reticulum stress, alterations to bile canaliculi dynamics and destruction to lipid membranes (Perez and Briz, 2009; Sharanek et al, 2016).…”

Section: Resultssupporting

confidence: 78%

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Differential toxic effects of bile acid mixtures in isolated mitochondria and physiologically relevant HepaRG cells

Penman

Sharma

Aerts

et al. 2019

Toxicology in Vitro

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Bile acids (BAs) are recognised as the causative agents of toxicity in drug-induced cholestasis (DIC). Research in isolated mitochondria and HepG2 cells have demonstrated BA-mediated mitochondrial dysfunction as a key mechanism of toxicity in DIC. However, HepG2 cells are of limited suitability for DIC studies as they do not express the necessary physiological characteristics. In this study, the mitotoxic potentials of BA mixtures were assessed in isolated mitochondria and a better-suited hepatic model, HepaRG cells. BAs induced structural alterations and a loss of mitochondrial membrane potential (MMP) in isolated mitochondria however, this toxicity did not translate to HepaRG cells. There were no changes in oxygen consumption rate, MMP or ATP levels in glucose and galactose media, indicating that there was no direct mitochondrial toxicity mediated via electron transport chain dysfunction in HepaRG cells. Assessment of key biliary transporters revealed that there was a time-dependent reduction in the expression and activity of multi-drug resistance protein 2 (MRP2), which was consistent with the induction of cytotoxicity in HepaRG cells. Overall, the findings from this study have demonstrated that mitochondrial dysfunction is not a mechanism of BA-induced toxicity in HepaRG cells.

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Section: Resultssupporting

confidence: 78%

Section: Resultssupporting

confidence: 78%

Differential toxic effects of bile acid mixtures in isolated mitochondria and physiologically relevant HepaRG cells

Penman

Sharma

Aerts

et al. 2019

Toxicology in Vitro

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“…Long-term gastroduodenal reflux may result in chronic inflammation (62), which may lead to muscle atrophy in the stomach tissue, intestinal erosion and the development of cancer (63). The accumulation of bile salts can contribute towards progressive liver damage and fibrosis; therefore, the levels of bile acids in the blood and tissues are highly regulated (64). Glycocholic acid, which is a combination of acetyl glycine (produced by cytidine 5′-diphosphocholine) and bile acid, serves as a detergent and promotes the absorption of fat as well as its own absorption, thereby preventing cholestasis (65).…”

Section: Discussionmentioning

confidence: 99%

A clinical metabolomics‑based biomarker signature as an approach for early diagnosis of gastric cardia adenocarcinoma

Sun

et al. 2019

Oncol Lett

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Gastric cardia adenocarcinoma (GCA) has a high mortality rate worldwide; however, current early diagnostic methods lack efficacy. Therefore, the aim of the present study was to identify potential biomarkers for the early diagnosis of GCA. Global metabolic profiles were obtained from plasma samples collected from 21 patients with GCA and 48 healthy controls using ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry. The orthogonal partial least squares discrimination analysis model was applied to distinguish patients with GCA from healthy controls and to identify potential biomarkers. Metabolic pathway analysis was performed using MetaboAnalyst (version 4.0) and revealed that ‘glycerophospholipid metabolism’, ‘linoleic acid metabolism’, ‘fatty acid biosynthesis’ and ‘primary bile acid biosynthesis’ were significantly associated with GCA. In addition, an early diagnostic model for GCA was established based on the relative levels of four key biomarkers, including phosphorylcholine, glycocholic acid, L-acetylcarnitine and arachidonic acid. The area under the receiver operating characteristic curve revealed that the diagnostic model had a sensitivity and specificity of 0.977 and 0.952, respectively. The present study demonstrated that metabolomics may aid the identification of the mechanisms underlying the pathogenesis of GCA. In addition, the proposed diagnostic method may serve as a promising approach for the early diagnosis of GCA.

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“…Previous publications have shown that a microtissue consisting of three cell lines HepaRG, THP-1, and hTERT-HSC can display a fibrotic phenotype when confronted with specific stimuli [ 8 , 12 , 13 ]. However, until now the response could only be assessed as a whole microtissue, without being able to discern between the contributions of each individual cell type.…”

Section: Introductionmentioning

confidence: 99%

Single Cell Gene Expression Analysis in a 3D Microtissue Liver Model Reveals Cell Type-Specific Responses to Pro-Fibrotic TGF-β1 Stimulation

Messner

Babrak

Titolo

et al. 2021

IJMS

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3D cell culture systems are widely used to study disease mechanisms and therapeutic interventions. Multicellular liver microtissues (MTs) comprising HepaRG, hTERT-HSC and THP-1 maintain multicellular interactions and physiological properties required to mimic liver fibrosis. However, the inherent complexity of multicellular 3D-systems often hinders the discrimination of cell type specific responses. Here, we aimed at applying single cell sequencing (scRNA-seq) to discern the molecular responses of cells involved in the development of fibrosis elicited by TGF-β1. To obtain single cell suspensions from the MTs, an enzymatic dissociation method was optimized. Isolated cells showed good viability, could be re-plated and cultured in 2D, and expressed specific markers determined by scRNA-seq, qRT-PCR, ELISA and immunostaining. The three cell populations were successfully clustered using supervised and unsupervised methods based on scRNA-seq data. TGF-β1 led to a fibrotic phenotype in the MTs, detected as decreased albumin and increased αSMA expression. Cell-type specific responses to the treatment were identified for each of the three cell types. They included HepaRG damage characterized by a decrease in cellular metabolism, prototypical inflammatory responses in THP-1s and extracellular matrix remodeling in hTERT-HSCs. Furthermore, we identified novel cell-specific putative fibrosis markers in hTERT-HSC (COL15A1), and THP-1 (ALOX5AP and LAPTM5).

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Bile salts regulate CYP7A1 expression and elicit a fibrotic response and abnormal lipid production in 3D liver microtissues

Cited by 13 publications

References 67 publications

Differential toxic effects of bile acid mixtures in isolated mitochondria and physiologically relevant HepaRG cells

Differential toxic effects of bile acid mixtures in isolated mitochondria and physiologically relevant HepaRG cells

A clinical metabolomics‑based biomarker signature as an approach for early diagnosis of gastric cardia adenocarcinoma

Single Cell Gene Expression Analysis in a 3D Microtissue Liver Model Reveals Cell Type-Specific Responses to Pro-Fibrotic TGF-β1 Stimulation

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