Identification of MicroRNAs That Control Lipid Droplet Formation and Growth in Hepatocytes via High-Content Screening

Whittaker, Ross; Loy, Patricia A.; Sisman, Eugene; Suyama, Eigo; Aza-Blanc, Pedro; Ingermanson, Randall; Price, Jeffrey H.; McDonough, Patrick M.

doi:10.1177/1087057110374991

Cited by 59 publications

(50 citation statements)

References 35 publications

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“…Although miR-181d has not yet been investigated in oncologic research, it is shown to play a role in lipid deposition and proliferation of hepatocyte (26). Our result suggests that miR-181d may play an antioncogenic role in pancreatic cancer.…”

Section: Discussionsupporting

confidence: 47%

MicroRNAs Associated with Mitogen-Activated Protein Kinase in Human Pancreatic Cancer

Ikeda

Tanji

Makino

et al. 2012

Molecular Cancer Research

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Aberrant expression of microRNAs (miRNA) is associated with phenotypes of various cancers, including pancreatic cancer. However, the mechanism of the aberrant expression is largely unknown. Activation of the mitogen-activated protein kinase (MAPK) signaling pathway plays a crucial role in gene expression related to the malignant phenotype of pancreatic cancer. Hence, we studied the role of MAPK in the aberrant expression of miRNAs in pancreatic cancer cells. The alterations in expression of 183 miRNAs induced by activation or inactivation of MAPK were assayed in cultured pancreatic cancer cells and HEK293 cells by means of the quantitative real-time PCR method. We found that four miRNAs, namely, miR-7-3, miR-34a, miR-181d, and miR-193b, were preferentially associated with MAPK activity. Among these miRNAs, miR-7-3 was upregulated by active MAPK, whereas the others were downregulated. Promoter assays indicated that the promoter activities of the host genes of miR-7-3 and miR-34a were both downregulated by alteration in MAPK activity. Exogenous overexpression of the MAPK-associated miRNAs had the effect of inhibition of the proliferation of cultured pancreatic cancer cells; miR-193b was found to exhibit the most remarkable inhibition. A search for target genes of miR-193b led to identification of CCND1, NT5E, PLAU, STARD7, STMN1, and YWHAZ as the targets. Translational suppression of these genes by miR-193b was confirmed by reporter assay. These results indicate that activation of MAPK may play a significant role in aberrant expression of miRNAs and their associated phenotypes in pancreatic cancer. Mol Cancer Res; 10(2); 259-69. Ó2011 AACR.

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Section: Discussionsupporting

confidence: 47%

MicroRNAs Associated with Mitogen-Activated Protein Kinase in Human Pancreatic Cancer

Ikeda

Tanji

Makino

et al. 2012

Molecular Cancer Research

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“…Interestingly, miR-181d has been reported to have a general role in regulating lipid content of hepatocytes via targeting Adamts5, which functions similarly with Adamts1. 52 Besides, miR-181d shares the same seed sequence with miR-181a, in view of which we supposed that miR-181d might participate in adipogenesis by targeting Adamts1. Our data confirmed that miR-181d promotes adipocyte lineage commitment by regulating Adamts1-ECM-FAK-ERK axis.…”

Section: Discussionmentioning

confidence: 99%

The miR-181d-regulated metalloproteinase Adamts1 enzymatically impairs adipogenesis via ECM remodeling

Chen

Ning

et al. 2016

Cell Death Differ

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The extracellular matrix (ECM) maintenance is crucial to the structural integrity of adipocytes and whole adipose tissue formation. However, the potential impact of the ECM on adipocyte lineage commitment is unclear. Herein, we demonstrate that forced expression of matrix-associated metalloproteinase Adamts1 (a disintegrin and metalloproteinase with thrombospondin motifs 1), which we show is targeted by microRNA-181d (miR-181d) during BMP4-induced adipocytic lineage commitment, markedly impairs adipocyte commitment. Conversely, siRNA-induced inhibition of Adamts1 promotes adipocyte commitment. Adamst1 metalloprotease activity is required for this inhibition and is determined to function via remodeling ECM components followed by activating FAK-ERK signaling pathway during the commitment process. Furthermore, ablation of Adamts1 in adipose tissue increases adipose tissue mass, reduces insulin sensitivity, and disrupts lipid homeostasis. This finding is consistent with Adamts1 decreased expression in the adipose tissue of obese mice and an inverse correlation of Adamts1 expression with body mass index in humans. Collectively, our results indicate that Adamts1 acts as an ECM 'modifier', with miR-181d-induced downregulation, that regulates adipocyte lineage commitment and obesity.

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“…miR-181d has been shown to decrease lipid droplets, and to reduce cellular triglycerides and cholesterol ester in cell culture [9] . In our study, serum levels of miR-181d were decreased in NAFLD by 2.49-fold compared to controls.…”

Section: 05) and Further Confirmed By Sam Test (Q < 5%)mentioning

confidence: 99%

“…miR-122 was significantly underexpressed in liver samples of NASH subjects compared to controls and miR-34a was significantly overexpressed [5] . miR-181d may play a role in regulating the lipid content of hepatocytes [9] . miR-197 and miR-99, in the visceral adipose tissue, were significantly associated with pericellular fibrosis in NAFLD [10] .…”

Section: Introductionmentioning

confidence: 99%

Circulating microRNAs in patients with non-alcoholic fatty liver disease

Celıkbılek¹,

Başkol²,

Taheri³

et al. 2014

WJH

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AIM:To identify novel non-invasive biomarkers for non-alcoholic fatty liver disease (NAFLD). METHODS:Twenty patients with histologically proven NAFLD and 20 controls were included. All NAFLD cases were scored using the NAFLD activity score. The relative expressions of miR-197, miR-146b, miR-10b, miR181d, miR-34a, miR-122, miR-99a and miR-29a were analyzed using real-time polymerase chain reaction. RESULTS:Serum levels of miR-181d, miR-99a, miR-197 and miR-146b were significantly lower in biopsy-proven NAFLD patients than in the healthy controls. Serum levels of miR-197 and miR-10b were inversely correlated with degree of inflammation and miR-181d and miR99a were inversely correlated with serum gamma glutamyl transferase levels in non-alcoholic steatohepatitis patients. CONCLUSION:NAFLD is associated with altered serum miRNA expression pattern. This study provides clues for defining the non-invasive diagnosis of NAFLD.© 2014 Baishideng Publishing Group Inc. All rights reserved.Key words: Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; MicroRNA; Noninvasive; Serum markers Core tip: Due to the limitations of liver biopsy, the use of non-invasive markers has emerged in recent years. MicroRNAs (miRNAs) are a class of naturally occurring small noncoding RNAs that regulate gene expression. Altered miRNA expression has been reported in animal and human liver samples in non-alcoholic fatty liver disease (NAFLD). There is, however, only limited information on their detection in blood and their correlation with histological disease severity in patients with NAFLD. For this reason, we measured the serum levels of some miRNAs in non-alcoholic steatohepatitis (NASH) patients. Of these microRNAs, miR-181d, miR99a, miR-197 and miR-146b were expressed at lower levels in NASH patients than in controls. Serum levels of miR-197 and miR-10b were inversely correlated with degree of inflammation and miR-181d and miR-99a were inversely correlated with serum gamma glutamyl transferase levels in NASH patients. Circulating microRNAs in patients with non-alcoholic fatty liver disease 613 Celikbilek M, Baskol M, Taheri S, Deniz K, Dogan S, Zararsız G, Gursoy S, Guven K, Ozbakır O, Dundar M, Yucesoy M. Circulating microRNAs in patients with non-alcoholic fatty liver disease. ORIGINAL ARTICLE

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Identification of MicroRNAs That Control Lipid Droplet Formation and Growth in Hepatocytes via High-Content Screening

Cited by 59 publications

References 35 publications

MicroRNAs Associated with Mitogen-Activated Protein Kinase in Human Pancreatic Cancer

MicroRNAs Associated with Mitogen-Activated Protein Kinase in Human Pancreatic Cancer

The miR-181d-regulated metalloproteinase Adamts1 enzymatically impairs adipogenesis via ECM remodeling

Circulating microRNAs in patients with non-alcoholic fatty liver disease

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