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Colon Epithelial MicroRNA Network in Fatty Liver 时间:2018-09-26 22:06 来源:未知作者:admin 点击: 次 Abstract:Background & Aims. Intestinal barrier alterations are associated with fatty liver (FL) and metabolic syndrome (MetS), but microRNA (miR) signaling pathways in MetS-FL pathogenesis remain unclear. This study investigates an epithelial-focused miR network in colorectal cell models based on the previously reported MetS-FL miR trio of hsa-miR-142-3p, hsa-miR-18b, and hsa-miR-890. Methods. Each miR mimic construct of MetS-FL miR trio was transfected into human colorectal cells, CRL-1790 or Caco-2. Global miRNome changes posttransfection were profiled (nCounter® Human v3 miRNA, NanoString Technologies). Changes in barrier (transepithelial electrical resistance, TEER) and epithelial cell junction structure (Occludin and Zona Occludens-1/ZO-1 immunofluorescence staining-confocal microscopy) were examined pre- and posttransfection in Caco-2 cell monolayers. A signaling network was constructed from the MetS-FL miR trio, MetS-FL miR-induced colorectal miRNome changes, ZO-1, and Occludin. Results. Transfection of CRL-1790 cells with each MetS-FL miR mimic led to global changes in the cellular miRNome profile, with 288 miRs being altered in expression by more than twofold. Eleven miRs with known cytoskeletal and metabolic roles were commonly altered in expression by all three miR mimics. Transfection of Caco-2 cell monolayers with each MetS-FL miR mimic induced barrier-associated TEER variations and led to structural modifications of ZO-1 and Occludin within epithelial cell junctions. Pathway analysis incorporating the MetS-FL miR trio, eleven common target miRs, ZO-1, and Occludin revealed a signaling network centered on TNF and AKT2, which highlights injury, inflammation, and hyperplasia. Conclusions. Colon-specific changes in epithelial barriers, cell junction structure, and a miRNome signaling network are described from functional studies of a MetS-FL miR trio signature.
1. Introduction
Metabolic Syndrome (MetS) arises from systemic metabolic perturbations characterized by dyslipidemia and central obesity [1]. MetS is associated with an increased risk of developing cardiovascular disease, liver fibrosis and cancer, colon cancer, and breast cancer [2–5]. MetS characteristics are highly prevalent among individuals with nonalcoholic fatty liver disease (NAFLD), particularly those who are obese (Body Mass Index or BMI ≥ 30) or have insulin resistance [6]. A meta-analysis of studies demonstrated that NAFLD patients had increased intestinal permeability compared to healthy controls. Intestinal inflammation and upregulation of tumor necrosis factor-α (TNFα), common in obese individuals with MetS and NAFLD, are also associated with intestinal leakage [7]. Pathophysiology of MetS and NAFLD has been attributed to changes in intestinal epithelial barriers, leading to altered intestinal permeability and translocation of microbes or microbial products, such as lipopolysaccharide (LPS) [8, 9]. Structural proteins, such as ZO-1 and Occludin, compose a cytoskeletal-supported cell junction network that maintains transport across the intestinal epithelial barrier and regulates permeability during normal physiology [10, 11]. Expression and localization of these structural proteins are known to be regulated by certain microRNAs (miRs), such as miR-142-3p, which regulates Rac1 [12]. We previously reported altered expression of miR-142-3p, miR-18b, and miR-890 in a cohort of patients with fatty liver (FL), who also met established criteria for MetS as defined by the International Diabetes Federation [1]. Also altered in this cohort were the expressions of mRNAs related to hepatocellular carcinoma progression pathways of adhesion, invasion, and metastasis [13]. Thus, these three miRs (hsa-miR-142-3p, hsa-miR-18b, and hsa-miR-890) may be indicators of epithelial barrier functional modifications in metabolically related MetS-FL.