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.

Adipogenesis Regulation and Endocrine Disruptors: Emerging Insights in Obesity

“…CHOP10 is a protein that increases its expression in response to the stress of the endoplasmic reticulum produced by the incorrect folding of proteins. Similarly, Beezhold et al [50] showed that arsenic can increase the expression of microRNA, miR-29b, involved in the regulation of the cell cycle and in the increase in the expression of cyclin D1, which results in inhibition of the differentiation towards the fat cell.…”

A State-of-the-Science Review of Arsenic’s Effects on Glucose Homeostasis in Experimental Models

“…C3H 10T1/2 preadipocytes exposed to sodium arsenite (6 mM) for 8 wk also experienced altered morphology and impaired differentiation (Trouba et al 2000). Arsenite-treated human hMSCs (1 lM for 24 and 48 h) exhibited significantly altered function of noncoding microRNA involved in adipogenesis (Beezhold et al 2017;Renu et al 2018). Both culture adipocytes and primary hMSCs isolated from mice treated with arsenite in vivo (100-250 ppb) increased microRNA 29 (miR-29) and cyclin D1 (CCND1) expression, furthering cell growth rather than adipogenic differentiation (Beezhold et al 2017).…”

Role of miR‐31 and SATB2 in arsenic‐induced malignant BEAS‐2B cell transformation

“…In consideration of their biological and epigenetic importance, disruptions in miRNA expression have been implicated in various diseases including cardiovascular disorders and cancer (Calin et al, 2005). Several studies have reported that arsenic exposure causes changes in miRNA expression (Marsit et al, 2006; Sturchio et al, 2014; Ren et al, 2016; Beezhold et al, 2017). Examples of arsenic-deregulated miRNAs include miR-29, -183, -192, etc.…”

“…42 Several studies have reported that arsenic exposure causes changes in miRNA expression. [43][44][45][46] Examples of arsenic-deregulated miRNAs include miR-29, -183, -192, etc. 45,46 Here we report for the first time that arsenic is able to trigger the down-regulation of miR-31, a known negative regulator of SATB2.…”

“…[43][44][45][46] Examples of arsenic-deregulated miRNAs include miR-29, -183, -192, etc. 45,46 Here we report for the first time that arsenic is able to trigger the down-regulation of miR-31, a known negative regulator of SATB2. [47][48][49] Using human bronchial epithelial cells, our study provides a novel mechanism that illustrates the functional roles of miR-31 in suppressing SATB2 expression and thereby preventing cell transformation.…”