Journal Article

Tributyltin chloride (TBT) induces RXRA down-regulation and lipid accumulation in human liver cells

Stossi, Fabio, Dandekar, Radhika D., Foulds, Charles E., Lavere, Philip, Mancini, Michael A., Mancini, Maureen G., Johnson, Hannah

2019

Overview

A subset of environmental chemicals acts as \"obesogens\" as they increase adipose mass and lipid content in livers of treated rodents. One of the most studied class of obesogens are the tin-containing chemicals that have as a central moiety tributyltin (TBT), which bind and activate two nuclear hormone receptors, Peroxisome Proliferator Activated Receptor Gamma (PPARG) and Retinoid X Receptor Alpha (RXRA), at nanomolar concentrations. Here, we have tested whether TBT chloride at such concentrations may affect the neutral lipid level in two cell line models of human liver. Indeed, using high content image analysis (HCA), TBT significantly increased neutral lipid content in a time- and concentration-dependent manner. Consistent with the observed increased lipid accumulation, RNA fluorescence in situ hybridization (RNA FISH) and RT-qPCR experiments revealed that TBT enhanced the steady-state mRNA levels of two key genes for de novo lipogenesis, the transcription factor SREBF1 and its downstream enzymatic target, FASN. Importantly, pre-treatment of cells with 2-deoxy-D-glucose reduced TBT-mediated lipid accumulation, thereby suggesting a role for active glycolysis during the process of lipid accumulation. As other RXRA binding ligands can promote RXRA protein turnover via the 26S proteasome, TBT was tested for such an effect in the two liver cell lines. We found that TBT, in a time- and dose-dependent manner, significantly reduced steady-state RXRA levels in a proteasome-dependent manner. While TBT promotes both RXRA protein turnover and lipid accumulation, we found no correlation between these two events at the single cell level, thereby suggesting an additional mechanism may be involved in TBT promotion of lipid accumulation, such as glycolysis.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Accumulation / Adipocytes / Antifouling substances / Bioaccumulation / Biology and Life Sciences / Biotechnology / Cancer / Cell culture / Cell Line / Cell lines / Cellular biology / Chemicals / Chloride / Chlorides / Deoxyglucose - pharmacology / Dose-Response Relationship, Drug / Down-regulation / Down-Regulation - drug effects / Endocrinology / Environmental health / Enzymes / Fluorescence / Fluorescence in situ hybridization / Gene expression / Genes / Glucose / Glucose metabolism / Glycolysis / Hep G2 Cells / Hepatocytes / Hepatocytes - drug effects / Hepatocytes - metabolism / Hormones / Humans / Image analysis / Image processing / Immunoglobulins / In Situ Hybridization, Fluorescence / Informatics / Levels / Lipid Metabolism - drug effects / Lipids / Lipogenesis / Liver / Medical schools / Medicine / Medicine and Health Sciences / Messenger RNA / Metabolism / Metabolites / Microscopy / Nuclear receptors / Obesity / Organic chemistry / Peroxisome proliferator-activated receptors / Physical Sciences / Proteasome 26S / Protein binding / Protein turnover / Proteins / Receptors / Research and Analysis Methods / Retinoid X Receptor alpha - genetics / Retinoid X Receptor alpha - metabolism / Retinoid X receptor α / Ribonucleic acid / RNA / Rodents / Steady state / Stem cells / Time dependence / Tin / Transcription (Genetics) / Trialkyltin Compounds - pharmacology / Tributyltin / Tributyltin chloride / Tributyltin compounds