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HepaRG cells are highly-differentiated human hepatoma cells, which are increasingly recognized as a convenient cellular model for in vitro evaluation of hepatic metabolism, transport, and/or toxicity of drugs. The present study was designed to evaluate whether HepaRG cells can also be useful for studying drug-mediated inhibition of canalicular and/or sinusoidal hepatic efflux of bile acids, which constitutes a major mechanism of drug-induced liver toxicity. For this purpose, HepaRG cells, initially loaded with the bile acid taurocholate (TC), were reincubated in TC-free transport assay medium, in the presence or absence of calcium or drugs, before analysis of TC retention. This method allowed us to objectivize and quantitatively measure biliary and sinusoidal efflux of TC from HepaRG cells, through distinguishing cellular and canalicular compartments. In particular, time-course analysis of the TC-free reincubation period of HepaRG cells, that is, the efflux period, indicated that a 20 min-efflux period allowed reaching biliary and sinusoidal excretion indexes for TC around 80% and 60%, respectively. Addition of the prototypical cholestatic drugs bosentan, cyclosporin A, glibenclamide, or troglitazone during the TC-free efflux phase period was demonstrated to markedly inhibit canalicular and sinusoidal secretion of TC, whereas, by contrast, incubation with the noncholestatic compounds salicylic acid or flumazenil was without effect. Such data therefore support the use of human HepaRG cells for in vitro predicting drug-induced liver toxicity (DILI) due to the inhibition of hepatic bile acid secretion, using a biphasic TC loading/efflux assay.
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http://dx.doi.org/10.1002/bdd.2333 | DOI Listing |
Arch Toxicol
December 2024
Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands.
Propiconazole is a triazole fungicide previously shown to induce triglyceride accumulation in human liver HepaRG cells, potentially via activation of the Pregnane X Receptor (PXR). However, whether propiconazole can disrupt hepatic and whole-body metabolism in vivo is currently unknown. Therefore, we aimed to examine the metabolic effects of propiconazole in the context of metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, and insulin resistance.
View Article and Find Full Text PDFMicrobes Infect
December 2024
Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany; Institute of Virology, Helmholtz Zentrum München, Munich, Germany. Electronic address:
Human endogenous retroviruses (HERVs), which are normally silenced by methylation or mutation, can be reactivated by a variety of environmental factors, including infection with exogenous viruses. In this work, we investigated the transcriptional activity of HERVs following infection of human liver cells (HepaRG) with human adenovirus C serotype 5 (HAdV-C5). HAdV-C5 infection results in reactivation of several HERV groups as well as differentially expressed genes.
View Article and Find Full Text PDFInt J Mol Sci
November 2024
Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A1, Canada.
L-arginine: glycine amidinotransferase (AGAT) gained academic interest as the rate-limiting enzyme in creatine biosynthesis and its role in the regulation of creatine homeostasis. Of clinical relevance is the diagnosis of patients with AGAT deficiency but also the potential role of AGAT as therapeutic target for the treatment of another creatine deficiency syndrome, guanidinoacetate N-methyltransferase (GAMT) deficiency. Applying a stable isotope-labeled substrate method, we utilized ARG 15N (ARG-δ2) and GLY 13C15N (GLY-δ3) to determine the rate of 1,2-13C,15N guanidinoacetate (GAA-δ5) formation to assess AGAT activity in various mouse tissue samples and human-derived cells.
View Article and Find Full Text PDFNutrients
December 2024
Laboratory of Molecular Medicine, National Institute of Gastroenterology IRCCS "S. de Bellis", Via Turi 27, Castellana Grotte, 70013 Bari, Italy.
Very low-calorie ketogenic diets (VLCKD) are an effective weight-loss strategy for obese individuals, reducing risks of liver conditions such as non-alcoholic steatohepatitis and fibrosis. Small extracellular vesicles (sEVs) are implicated in liver fibrosis by influencing hepatic cell phenotypes and contributing to liver damage. This study investigates sEVs derived from serum of 60 obese adults categorized into low fibrosis risk (LR) and intermediate/high fibrosis risk (IHR) groups based on FibroScan elastography (FIB E scores, limit value 8 kPa) and all participants underwent an 8-week VLCKD intervention.
View Article and Find Full Text PDFFEBS Open Bio
December 2024
Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology IRCCS "Saverio de Bellis", Castellana Grotte, Italy.
The condition of cellular senescence has specific features, including an altered lipid metabolism. Delta-9 desaturase (Δ9) catalyzes the conversion of saturated fatty acids, such as palmitic acid and stearic acid, into their monounsaturated forms, palmitoleic and oleic acid, respectively. Δ9 activity is important for most lipid functions, such as membrane fluidity, lipoprotein metabolism and energy storage.
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