title: Regulation of cyclin D1 by arsenic and microRNA inhibits adipogenesis.
abstract: Low-dose chronic exposure to arsenic in drinking water represents a global public health concern with established risks for metabolic and cardiovascular disease, as well as cancer. While the linkage between arsenic and disease is strong, further understanding of the molecular mechanisms of its pathogenicity is required. Previous reports demonstrated the ability of arsenic to interfere with adipogenesis, which may mediate its effects in promoting metabolic disease. We hypothesized that microRNA are important regulators of most if not all mesenchymal stem cell processes that are dysregulated by arsenic exposure to impair lipogenesis. Arsenic increased the expression of miR-29b in white adipose tissue, as well as human mesenchymal stem cells (hMSCs) isolated from adipose tissue. Exposing hMSCs to arsenic increased abundance of miR-29b and cyclin D1 to promote proliferation over differentiation. Paradoxically, inhibition of miR-29b enhanced the inhibitory effect of arsenic on differentiation. This paradox was attributed to a requirement for miR-29 in regulating cyclin D1 expression as stable inhibition of miR-29b eliminated the cyclic pattern of cyclin D1 expression. Temporal regulation of cyclin D1 is critical for adipogenic differentiation, and the data suggest a paradigm where arsenic disruption of miR-29b regulatory pathways impairs adipogenic differentiation and ultimately adipose metabolic homeostasis.
authors.affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Beezhold
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Linda R
authors.initials: LR
authors.lastname: Klei
authors.affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15219, USA. Electronic address: aab20@pitt.edu.
authors.forename: Aaron
authors.initials: A
authors.lastname: Barchowsky
mesh_terms: D050156:Adipogenesis / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D018053:Arsenites; C530105:Ccnd1 protein, mouse; C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D014874:Water Pollutants, Chemical; D019938:Cyclin D1; C015001:arsenite
keywords: Adipogenesis; Arsenic; Cyclin D1; HuR; Mesenchymal stem cell; microRNA