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


Autoři: Fabio Stossi aff001;  Radhika D. Dandekar aff002;  Hannah Johnson aff002;  Philip Lavere aff001;  Charles E. Foulds aff001;  Maureen G. Mancini aff001;  Michael A. Mancini aff001
Působiště autorů: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States of America aff001;  Integrated Microscopy Core, Baylor College of Medicine, Houston, TX, United States of America aff002;  GCC Center for Advanced Microscopy and Image Informatics, Houston, TX, United States of America aff003;  Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, United States of America aff004;  Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, United States of America aff005;  Dan L. Duncan Comprehensive Cancer Center; Baylor College of Medicine, Houston, TX, United States of America aff006;  Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, United States of America aff007
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224405

Souhrn

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.

Klíčová slova:

Chlorides – Image analysis – Immunofluorescence – Lipid analysis – Lipids – Obesity – RNA hybridization – Lipogenesis


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