👤 Rosemarie Marchan

Hyperlipidemia is a complex lipid metabolism disorder defined as an abnormal increase in circulating levels of one or more plasma lipids and lipoproteins. Triton WR-1339-induced hyperlipidemia model is one of the most commonly used acute models for hyperlipidemia induction in research. However, the metabolic alteration induced by Triton WR-1339 remains unclear. This study aimed to identify potential biomarkers associated with the Triton WR-1339-induced hyperlipidemia model. In addition, it aims to explore the underlying mechanisms of metabolic disturbances associated with hyperlipidemia. Male Wistar rats were administered Triton WR-1339 to induce hyperlipidemia. Plasma samples were collected for lipid assays and for metabolomics analysis using nuclear magnetic resonance spectroscopy. Gene expression in liver, cardiac, and kidney tissues of key associated transporters including SLC16A1, SLC25A10, SLC5A3, and SLC7A8 and SDHA enzyme subunit was assessed using RT-PCR. In-silico analysis complemented experimental data using NEBION Genevestigator and STITCH databases for molecular interactions. Triton WR-1339 administration significantly elevated plasma triglycerides. Orthogonal partial least squares-discriminant analysis (OPLS-DA) demonstrated distinct metabolic profiles between control and model groups. Metabolomics results identified potential biomarkers (p < 0.05), including myo-inositol, succinate, creatine, glycine, serine, isoleucine and creatine phosphate, which all showed higher levels in hyperlipidemia group compared to control group while xanthine showed lower levels in hyperlipidemia group. Potential biomarkers were associated with inflammatory, oxidative stress responses, and abnormal lipid metabolism. Gene expression analysis revealed significant tissue-specific alterations including changes in the expression of SDHA in the liver, an upregulated SLC16A1 in cardiac tissue (in-silico and in-vivo), a downregulated SLC5A3 in cardiac tissue (in-vivo), an upregulated SLC25A10 in cardiac tissue (in-vivo) and differential in-silico expression of SLC25A10 across liver and kidney tissues. Further network analysis indicates that Triton WR-1339 may induce hyperlipidemia by significantly elevating triglyceride levels through the inhibition of LPL. Our findings identify a set of metabolites as potential biomarkers of hyperlipidemia development in the Triton WR-1339 model. Correlation between gene expression analysis and metabolic profiling results demonstrates a possible mechanism in which Triton WR-1339 leads to metabolic disruption during hyperlipidemia induction. Show less

A long-term goal of numerous research projects is to identify biomarkers for in vitro systems predicting toxicity in vivo. Often, transcriptomics data are used to identify candidates for further evaluation. However, a systematic directory summarizing key features of chemically influenced genes in human hepatocytes is not yet available. To bridge this gap, we used the Open TG-GATES database with Affymetrix files of cultivated human hepatocytes incubated with chemicals, further sets of gene array data with hepatocytes from human donors generated in this study, and publicly available genome-wide datasets of human liver tissue from patients with non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular cancer (HCC). After a curation procedure, expression data of 143 chemicals were included into a comprehensive biostatistical analysis. The results are summarized in the publicly available toxicotranscriptomics directory ( http://wiki.toxbank.net/toxicogenomics-map/ ) which provides information for all genes whether they are up- or downregulated by chemicals and, if yes, by which compounds. The directory also informs about the following key features of chemically influenced genes: (1) Stereotypical stress response. When chemicals induce strong expression alterations, this usually includes a complex but highly reproducible pattern named 'stereotypical response.' On the other hand, more specific expression responses exist that are induced only by individual compounds or small numbers of compounds. The directory differentiates if the gene is part of the stereotypical stress response or if it represents a more specific reaction. (2) Liver disease-associated genes. Approximately 20 % of the genes influenced by chemicals are up- or downregulated, also in liver disease. Liver disease genes deregulated in cirrhosis, HCC, and NASH that overlap with genes of the aforementioned stereotypical chemical stress response include CYP3A7, normally expressed in fetal liver; the phase II metabolizing enzyme SULT1C2; ALDH8A1, known to generate the ligand of RXR, one of the master regulators of gene expression in the liver; and several genes involved in normal liver functions: CPS1, PCK1, SLC2A2, CYP8B1, CYP4A11, ABCA8, and ADH4. (3) Unstable baseline genes. The process of isolating and the cultivation of hepatocytes was sufficient to induce some stress leading to alterations in the expression of genes, the so-called unstable baseline genes. (4) Biological function. Although more than 2,000 genes are transcriptionally influenced by chemicals, they can be assigned to a relatively small group of biological functions, including energy and lipid metabolism, inflammation and immune response, protein modification, endogenous and xenobiotic metabolism, cytoskeletal organization, stress response, and DNA repair. In conclusion, the introduced toxicotranscriptomics directory offers a basis for a rationale choice of candidate genes for biomarker evaluation studies and represents an easy to use source of background information on chemically influenced genes. Show less