circRNA_0046366 inhibits hepatocellular steatosis by normalization of PPAR signaling

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Abstract

AIM

To investigate micro (mi)R-34a-antagonizing circular (circ)RNA that underlies hepatocellular steatosis.

METHODS

The effect of circRNA on miR-34a was recognized by the miRNA response element (MRE), and validated by the dual-luciferase reporter assay. Its association with hepatocellular steatosis was investigated in HepG2-based hepatocellular steatosis induced by free fatty acids (FFAs; 2:1 oleate:palmitate) stimulation. After normalization of the steatosis-related circRNA by expression vector, analysis of miR-34a activity, peroxisome proliferator-activated receptor (PPAR)α level, and expression of downstream genes were carried out so as to reveal its impact on the miR-34a/PPARα regulatory system. Both triglyceride (TG) assessment and cytopathological manifestations uncovered the role of circRNA in miR-34a-dependent hepatosteatogenesis.

RESULTS

Bioinformatic and functional analysis verified circRNA_0046366 to antagonize the activity of miR-34a via MRE-based complementation. In contrast to its lowered level during FFA-induced hepatocellular steatosis, circRNA_0046366 up-regulation abolished the miR-34a-dependent inhibition of PPARα that played a critical role in metabolic signaling pathways. PPARα restoration exerted transcriptional improvement to multiple genes responsible for lipid metabolism. TG-specific lipolytic genes [carnitine palmitoyltransferase 1A (CPT1A) and solute-carrier family 27A (SLC27A)] among these showed significant increase in their expression levels. The circRNA_0046366-related rebalancing of lipid homeostasis led to dramatic reduction of TG content, and resulted in the ameliorated phenotype of hepatocellular steatosis.

CONCLUSION

Dysregulation of circRNA_0046366/miR-34a/PPARα signaling may be a novel epigenetic mechanism underlying hepatocellular steatosis. circRNA_0046366 serves as a potential target for the treatment of hepatic steatosis.

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Most cited references 32

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The circular RNA Cdr1as, via miR-7 and its targets, regulates insulin transcription and secretion in islet cells

Huanyu Xu, Sen Guo, Wei Li … (2015)

Among the identified thousands of circular RNAs (circRNA) in humans and animals, Cdr1as (also known as CiRS-7) was recently demonstrated to act as a powerful miR-7 sponge/inhibitor in developing midbrain of zebrafish, suggesting a novel mechanism for regulating microRNA functions. MiR-7 is abundantly expressed in islet cells, but overexpressing miR-7 in transgenic mouse β cells causes diabetes. Therefore, we infer that Cdr1as expression may inhibit miR-7 function in islet cells, which in turn improves insulin secretion. Here, we show the first characterization of Cdr1as expression in islet cells, which was upregulated by long-term forskolin and PMA stimulation, but not high glucose, indicating the involvement of cAMP and PKC pathways. Remarkably, both insulin content and secretion were significantly increased by overexpression of Cdr1as in islet cells. We further identified a new target Myrip in the Cdr1as/miR-7 pathway that regulates insulin granule secretion, and also another target Pax6 that enhances insulin transcription. Taken together, our findings revealed the effects of the strongly interacting pair of Cdr1as/miR-7 on insulin secretion, which may become a new target for improving β cell function in diabetes.

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Emerging roles of circRNA_001569 targeting miR-145 in the proliferation and invasion of colorectal cancer

Huijun Xie, Xiaoli Ren, Sainan Xin … (2016)

Circular RNAs (circRNAs), a large class of RNAs, have recently shown huge capabilities as gene regulators in mammals. Some of them bind with microRNAs (miRNAs) and act as natural miRNA sponges to inhibit related miRNAs’ activities. Here we showed that hsa_circ_001569 acted as a positive regulator in cell proliferation and invasion of colorectal cancer (CRC). Moreover, hsa_circ_001569 was identified as a sponge of miR-145 and up-regulated miR-145 functional targets E2F5, BAG4 and FMNL2. In CRC tissues, circ_001569 negatively correlated with miR-145, and miR-145 correlated negatively with E2F5, BAG4 and FMNL2 expressions. Our study reveals a novel regulatory mechanism of circ_001569 in cell proliferation and invasion in CRC, provides a comprehensive landscape of circ_001569 that will facilitate further biomarker discoveries in the progression of CRC.

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A novel identified circular RNA, circRNA_010567, promotes myocardial fibrosis via suppressing miR-141 by targeting TGF-β1.

Bing Zhou, Jian-Wu Yu (2017)

Circular RNAs (circRNAs) are a novel type of endogenous noncoding RNA gaining research interest in recent years. Despite this increase in interest, the mechanism of circRNAs in the pathogenesis of multiple cardiovascular diseases, particularly myocardial fibrosis, is rarely reported. In the following study, the expression profiles and potential mechanisms of circRNAs in mice myocardial fibrosis models in vitro are investigated. Previous research examining circRNA expression profiles of diabetic db/db mice myocardium using circRNA microarray found 43 circRNAs were abnormally expressed, including 24 up-regulated circRNAs and 19 down-regulated circRNAs. Furthermore, circRNA_010567 was markedly up-regulated in diabetic mice myocardium and cardiac fibroblasts (CFs) treated with Ang II. Bioinformatics analysis predicted circRNA_010567, sponge miR-141 and miR-141 directly target TGF-β1, which was validated by dual-luciferase assay. Subsequently, functional experiments revealed circRNA_010567 silencing could up-regulate miR-141 and down-regulate TGF-β1 expression, and suppress fibrosis-associated protein resection in CFs, including Col I, Col III and α-SMA. Results demonstrate the circRNA_010567/miR-141/TGF-β1 axis plays an important regulatory role in the diabetic mice myocardial fibrosis model. The present study characterizes a new function of circRNA in the pathogenesis of myocardial fibrosis in a diabetic mouse model, providing novel insight for circRNA-miRNA-mRNA in cardiovascular disease.

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Author and article information

Contributors

Xing-Ya Guo

Fang Sun

Jian-Neng Chen

Yu-Qin Wang

Qin Pan

Jian-Gao Fan

Journal

Journal ID (nlm-ta): World J Gastroenterol

Journal ID (iso-abbrev): World J. Gastroenterol

Journal ID (publisher-id): WJG

Title: World Journal of Gastroenterology

Publisher: Baishideng Publishing Group Inc

ISSN (Print): 1007-9327

ISSN (Electronic): 2219-2840

Publication date (Print): 21 January 2018

Publication date (Electronic): 21 January 2018

Volume: 24

Issue: 3

Pages: 323-337

Affiliations

Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China

Department of Hepatology, Zhengxing Hospital, Zhangzhou 363000, Fujian Province, China

Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China

Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. panqin@ 123456xinhuamed.com.cn

Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China

Shanghai Key Laboratory of Children’s Digestion and Nutrition, Shanghai 200092, China

Author notes

Author contributions: Pan Q and Fan JG should be as the co-corresponding authors; Guo XY, Sun F and Chen JN contributed equally to this paper; Pan Q and Fan JG conceived and designed the experiments; Guo XY and Sun F performed the experiments; Chen JN, Wang YQ and Pan Q analyzed the data; Pan Q wrote the paper.

Correspondence to: Qin Pan, MD, PhD, Professor, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Kongjiang Road NO 1665, Yangpu District, Shanghai 200092, China. panqin@ 123456xinhuamed.com.cn

Telephone: +86-21-25078999 Fax: +86-21-25077340

Article

Other ID: jWJG.v24.i3.pg323

DOI: 10.3748/wjg.v24.i3.323

PMC ID: 5776394

PubMed ID: 29391755

SO-VID: 8c7239bb-f908-4559-b425-0a9d90bc44ad

License:

This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

History

Date received : 7 October 2017

Date revision received : 15 November 2017

Date accepted : 27 November 2017

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circRNA_0046366 inhibits hepatocellular steatosis by normalization of PPAR signaling

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Abstract

AIM

METHODS

RESULTS

CONCLUSION

Related collections

Neuronal Signaling

Most cited references 32

The circular RNA Cdr1as, via miR-7 and its targets, regulates insulin transcription and secretion in islet cells

Emerging roles of circRNA_001569 targeting miR-145 in the proliferation and invasion of colorectal cancer

A novel identified circular RNA, circRNA_010567, promotes myocardial fibrosis via suppressing miR-141 by targeting TGF-β1.

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Cited by 42

Most referenced authors 1,657