The Roles and Mechanisms of lncRNAs in Liver Fibrosis

Long non-coding RNAs (lncRNAs) can potentially regulate all aspects of cellular activity including differentiation and development, metabolism, proliferation, apoptosis, and activation, and benefited from advances in transcriptomic and genomic research techniques and database management technologies, its functions and mechanisms in physiological and pathological states have been widely reported. Liver fibrosis is typically characterized by a reversible wound healing response, often accompanied by an excessive accumulation of extracellular matrix. In recent years, a range of lncRNAs have been investigated and found to be involved in several cellular-level regulatory processes as competing endogenous RNAs (ceRNAs) that play an important role in the development of liver fibrosis. A variety of lncRNAs have also been shown to contribute to the altered cell cycle, proliferation profile associated with the accelerated development of liver fibrosis. This review aims to discuss the functions and mechanisms of lncRNAs in the development and regression of liver fibrosis, to explore the major lncRNAs involved in the signaling pathways regulating liver fibrosis, to elucidate the mechanisms mediated by lncRNA dysregulation and to provide new diagnostic and therapeutic strategies for liver fibrosis.

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The Roles and Mechanisms of lncRNAs in Liver Fibrosis

International Journal of Molecular Sciences ◽

10.3390/ijms21041482 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1482 ◽

Cited By ~ 5

Author(s):

Zhi He ◽

Deying Yang ◽

Xiaolan Fan ◽

Mingwang Zhang ◽

Yan Li ◽

...

Keyword(s):

Liver Fibrosis ◽

Hepatic Fibrosis ◽

Antisense Rna ◽

Transcriptome Profile ◽

Cellular Processes ◽

Gene And Protein Expression ◽

Wound Healing Response ◽

Competing Endogenous Rnas ◽

Matrix Accumulation ◽

Insight Into

Many studies have revealed that circulating long noncoding RNAs (lncRNAs) regulate gene and protein expression in the process of hepatic fibrosis. Liver fibrosis is a reversible wound healing response followed by excessive extracellular matrix accumulation. In the development of liver fibrosis, some lncRNAs regulate diverse cellular processes by acting as competing endogenous RNAs (ceRNAs) and binding proteins. Previous investigations demonstrated that overexpression of lncRNAs such as H19, maternally expressed gene 3 (MEG3), growth arrest-specific transcript 5 (GAS5), Gm5091, NR_002155.1, and HIF 1alpha-antisense RNA 1 (HIF1A-AS1) can inhibit the progression of liver fibrosis. Furthermore, the upregulation of several lncRNAs [e.g., nuclear paraspeckle assembly transcript 1 (NEAT1), hox transcript antisense RNA (Hotair), and liver-enriched fibrosis-associated lncRNA1 (lnc-LFAR1)] has been reported to promote liver fibrosis. This review will focus on the functions and mechanisms of lncRNAs, the lncRNA transcriptome profile of liver fibrosis, and the main lncRNAs involved in the signalling pathways that regulate hepatic fibrosis. This review provides insight into the screening of therapeutic and diagnostic markers of liver fibrosis.

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Non-coding RNA Associated Competitive Endogenous RNA Regulatory Network: Novel Therapeutic Approach in Liver Fibrosis

Current Gene Therapy ◽

10.2174/1566523219666191107113046 ◽

2019 ◽

Vol 19 (5) ◽

pp. 305-317 ◽

Cited By ~ 4

Author(s):

Farooq Riaz ◽

Dongmin Li

Keyword(s):

Liver Fibrosis ◽

Target Genes ◽

Signaling Cascades ◽

Circular Rnas ◽

Pathological Feature ◽

Non Coding Rna ◽

Overwhelming Evidence ◽

Competing Endogenous Rnas ◽

Non Coding Rnas ◽

Competitive Endogenous Rna

Liver fibrosis or scarring is the most common pathological feature caused by chronic liver injury, and is widely considered one of the primary causes of morbidity and mortality. It is primarily characterised by hepatic stellate cells (HSC) activation and excessive extracellular matrix (ECM) protein deposition. Overwhelming evidence suggests that the dysregulation of several noncoding RNAs (ncRNAs), mainly long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs) contributes to the activation of HSC and progression of liver fibrosis. These ncRNAs not only bind to their target genes for the development and regression of liver fibrosis but also act as competing endogenous RNAs (ceRNAs) by sponging with miRNAs to form signaling cascades. Among these signaling cascades, lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA are critical modulators for the initiation, progression, and regression of liver fibrosis. Thus, targeting these interacting ncRNA cascades can serve as a novel and potential therapeutic target for inhibition of HSC activation and prevention and regression of liver fibrosis.

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Stiffness is associated with hepatic stellate cell heterogeneity during liver fibrosis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00254.2021 ◽

2021 ◽

Author(s):

Enis Kostallari ◽

Bo Wei ◽

Delphine Sicard ◽

Jiahui Li ◽

Shawna A. Cooper ◽

...

Keyword(s):

Liver Fibrosis ◽

Focal Adhesion ◽

Hepatic Stellate Cell ◽

Stellate Cell ◽

Liver Stiffness ◽

Specific Protein ◽

Cellular Level ◽

Fibrotic Liver ◽

Soft Matrix

The fibrogenic wound-healing response in liver increases stiffness. Stiffness mechano-transduction in turn amplifies fibrogenesis. Here, we aimed to understand the distribution of stiffness in fibrotic liver, how it impacts hepatic stellate cell (HSC) heterogeneity and identify mechanisms by which stiffness amplifies fibrogenic responses. Magnetic resonance elastography and atomic force microscopy demonstrated a heterogenous distribution of liver stiffness at macroscopic and microscopic levels, respectively, in a carbon tetrachloride (CCl4) mouse model of liver fibrosis as compared to controls. High stiffness was mainly attributed to extracellular matrix dense areas. To identify a stiffness-sensitive HSC sub-population, we performed scRNA-seq on primary HSCs derived from healthy versus CCl4-treated mice. A sub-cluster of HSCs was matrix-associated with the most upregulated pathway in this sub-population being focal adhesion signaling, including a specific protein termed four and a half LIM domains protein 2 (FHL2). In vitro, FHL2 expression was increased in primary human HSCs cultured on stiff matrix as compared to HSCs on soft matrix. Moreover, FHL2 knockdown inhibited fibronectin and collagen 1 expression, whereas its overexpression promoted matrix production. In summary, we demonstrate stiffness heterogeneity at the whole organ, lobular, and cellular level which drives an amplification loop of fibrogenesis through specific focal adhesion molecular pathways.

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Genome-Wide Identification and Characterization of Long Non-Coding RNAs in Peanut

Genes ◽

10.3390/genes10070536 ◽

2019 ◽

Vol 10 (7) ◽

pp. 536 ◽

Cited By ~ 2

Author(s):

Xiaobo Zhao ◽

Liming Gan ◽

Caixia Yan ◽

Chunjuan Li ◽

Quanxi Sun ◽

...

Keyword(s):

Large Scale ◽

Target Genes ◽

Sequencing Data ◽

Regulatory Processes ◽

Genome Wide ◽

Non Coding Rnas ◽

Identification And Characterization ◽

Lower Expression ◽

Weighted Correlation

Long non-coding RNAs (lncRNAs) are involved in various regulatory processes although they do not encode protein. Presently, there is little information regarding the identification of lncRNAs in peanut (Arachis hypogaea Linn.). In this study, 50,873 lncRNAs of peanut were identified from large-scale published RNA sequencing data that belonged to 124 samples involving 15 different tissues. The average lengths of lncRNA and mRNA were 4335 bp and 954 bp, respectively. Compared to the mRNAs, the lncRNAs were shorter, with fewer exons and lower expression levels. The 4713 co-expression lncRNAs (expressed in all samples) were used to construct co-expression networks by using the weighted correlation network analysis (WGCNA). LncRNAs correlating with the growth and development of different peanut tissues were obtained, and target genes for 386 hub lncRNAs of all lncRNAs co-expressions were predicted. Taken together, these findings can provide a comprehensive identification of lncRNAs in peanut.

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Fighting Liver Fibrosis with Naturally Occurring Antioxidants

Planta Medica ◽

10.1055/a-0757-0008 ◽

2018 ◽

Vol 84 (18) ◽

pp. 1318-1333 ◽

Cited By ~ 3

Author(s):

Ligen Lin ◽

Fayang Zhou ◽

Shengnan Shen ◽

Tian Zhang

Keyword(s):

Oxidative Stress ◽

Liver Fibrosis ◽

Normal Liver ◽

Natural Antioxidants ◽

In Vivo Studies ◽

Lead Compounds ◽

Naturally Occurring ◽

Wound Healing Response

AbstractLiver fibrosis is a wound-healing response characterized by the accumulation of extracellular matrix following various liver injuries, which results in the deformation of the normal liver architecture and the development of liver cirrhosis and even hepatocellular carcinoma. Numerous in vitro and in vivo studies indicated that oxidative stress mediates the initiation and progression of liver fibrosis. Overaccumulation of reactive oxygen species disrupts macromolecules, induces necrosis and apoptosis of hepatocytes, stimulates the production of pro-fibrogenic mediators, and directly activates hepatic stellate cells, thereby resulting in liver damage and initiating liver fibrosis. Ameliorating oxidative stress is a potential therapeutic strategy for the treatment of liver fibrosis. Natural antioxidants have attracted increasing attention in treating liver fibrosis due to their safety and efficacy. In this review, the pathogenesis of liver fibrosis and the role of oxidative stress in liver fibrosis were discussed. Naturally occurring antioxidants that can treat and prevent liver fibrosis were summarized. Advances in clinical trials were also presented. The main purpose of this review is to provide a comprehensive and up-to-date knowledge from the biological importance of oxidative stress in liver fibrosis to representative antioxidants for treating liver fibrosis. Naturally occurring antioxidants show a potential for further investigations as lead compounds in fighting liver fibrosis.

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ceRNAs and ceRNA Networks in Normal and Malignant Hematopoiesis and Their Therapeutic Implications

Blood ◽

10.1182/blood.v122.21.sci-30.sci-30 ◽

2013 ◽

Vol 122 (21) ◽

pp. SCI-30-SCI-30

Author(s):

Pier Paolo Pandolfi

Keyword(s):

Cross Talk ◽

Conflicts Of Interest ◽

Therapeutic Implications ◽

Hematopoietic Malignancies ◽

Competing Endogenous Rnas ◽

Non Coding Rnas

Abstract We will discuss exciting new data regarding the role of pseudogenes, long intergenic non-coding RNAs (lincRNAs) and miRNAs in the pathogenesis of leukemia and lymphoma, as also studied in vivo in the mouse, and their therapeutic implications. We will also focus on competing endogenous RNAs (ceRNAs), circular(circ)-ceRNAs and pseudo-ceRNAs and give important attention to how understanding their cross-talk and the ceRNA language will facilitate efforts to deconvolute ceRNA networks and their role in the pathogenesis of hematopoietic malignancies. Disclosures: No relevant conflicts of interest to declare.

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Inflammasomes in Liver Fibrosis

Seminars in Liver Disease ◽

10.1055/s-0037-1601350 ◽

2017 ◽

Vol 37 (02) ◽

pp. 119-127 ◽

Cited By ~ 53

Author(s):

Fernando Alegre ◽

Pablo Pelegrin ◽

Ariel Feldstein

Keyword(s):

Cell Death ◽

Liver Fibrosis ◽

Cell Fate ◽

Disease Process ◽

Direct Effects ◽

Nonparenchymal Cells ◽

Danger Signals ◽

Cellular Target ◽

Wound Healing Response ◽

Central Elements

AbstractCell death and inflammation are two central elements in the development of liver fibrosis. Inflammasomes are intracellular multiprotein complexes expressed in both hepatocytes and nonparenchymal cells in the liver that are key regulators of inflammation and cell fate. They respond to cellular danger signals by activating caspase 1, releasing the proinflammatory cytokines IL-1β and IL-18, as well as initiating a novel pathway of programmed cell death termed “pyroptosis.” These processes can initiate and perpetuate an abnormal wound-healing response with the principle cellular target being the activation of hepatic stellate cells. From the various inflammasomes, the NLRP3 inflammasome has been increasingly implicated in the pathogenesis of chronic inflammatory liver diseases, including nonalcoholic steatohepatitis, a disease process that is soaring and has evolved as a primary cause of liver fibrosis and need for liver transplantation. In this review, the authors highlight the growing evidence for both indirect and direct effects of inflammasomes in triggering liver fibrosis as well as potential novel targets for antifibrotic therapies.

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α-fur, an antisense RNA gene to fur in the extreme acidophile Acidithiobacillus ferrooxidans

Microbiology ◽

10.1099/mic.0.073171-0 ◽

2014 ◽

Vol 160 (3) ◽

pp. 514-524 ◽

Cited By ~ 3

Author(s):

C. Lefimil ◽

E. Jedlicki ◽

D. S. Holmes

Keyword(s):

Acidithiobacillus Ferrooxidans ◽

Antisense Rna ◽

Cellular Level ◽

Antisense Strand ◽

Ferric Uptake Regulator ◽

Coding Region ◽

Non Coding Rna ◽

Non Coding Rnas ◽

Rapid Amplification ◽

Genetic Context

A large non-coding RNA, termed α-Fur, of ~1000 nt has been detected in the extreme acidophile Acidithiobacillus ferrooxidans encoded on the antisense strand to the iron-responsive master regulator fur (ferric uptake regulator) gene. A promoter for α-fur was predicted bioinformatically and validated using gene fusion experiments. The promoter is situated within the coding region and in the same sense as proB, potentially encoding a glutamate 5-kinase. The 3′ termination site of the α-fur transcript was determined by 3′ rapid amplification of cDNA ends to lie 7 nt downstream of the start of transcription of fur. Thus, α-fur is antisense to the complete coding region of fur, including its predicted ribosome-binding site. The genetic context of α-fur is conserved in several members of the genus Acidithiobacillus but not in all acidophiles, indicating that it is monophyletic but not niche specific. It is hypothesized that α-Fur regulates the cellular level of Fur. This is the fourth example of an antisense RNA to fur, although it is the first in an extreme acidophile, and underscores the growing importance of cis-encoded non-coding RNAs as potential regulators involved in the microbial iron-responsive stimulon.

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Genetic control of growth

Acta Endocrinologica ◽

10.1530/eje.1.01797 ◽

2005 ◽

Vol 152 (1) ◽

pp. 11-31 ◽

Cited By ~ 65

Author(s):

Primus E Mullis

Keyword(s):

Cell Biology ◽

Molecular Level ◽

Cellular Level ◽

Hormone Production ◽

Regulatory Processes ◽

Regulatory Systems ◽

Expression Of Genes ◽

Pathophysiological Role ◽

Level I ◽

Made In

The application of the powerful tool molecular biology has made it possible to ask questions not only about hormone production and action but also to characterize many of the receptor molecules that initiate responses to the hormones. We are beginning to understand how cells may regulate the expression of genes and how hormones intervene in regulatory processes to adjust the expression of individual genes. In addition, great strides have been made in understanding how individual cells talk to each other through locally released factors to coordinate growth, differentiation, secretion, and other responses within a tissue. In this review I (1) focus on developmental aspects of the pituitary gland, (2) focus on the different components of the growth hormone axis and (3) examine the different altered genes and their related growth factors and/or regulatory systems that play an important physiological and pathophysiological role in growth. Further, as we have already entered the ‘post-genomic’ area, in which not only a defect at the molecular level becomes important but also its functional impact at the cellular level, I concentrate in the last part on some of the most important aspects of cell biology and secretion.

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