Hepatitis C virus induced up-regulation of microRNA-27: A novel mechanism for hepatic steatosis

Singaravelu, Ragunath; Chen, Ran; Lyn, Rodney K.; Jones, Daniel M.; O’Hara, Shifawn; Rouleau, Y; Cheng, Jordan; Srinivasan, Prashanth; Nasheri, Neda; Russell, Rodney S.; Tyrrell, D. Lorne; Pezacki, John Paul

doi:10.1002/hep.26634

Cited by 100 publications

(90 citation statements)

References 44 publications

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“…This subset of miRNAs included miR-122, which is a key player in HCV infection and liver disease (reviewed in reference 4); miR-21-5p, which has consistently been shown to be implicated in HCV infection and liver disease (47)(48)(49); and miR-146a-5p, a well-known immunoregulatory miRNA further described to be associated with liver fibrosis and HCC (54,55,(64)(65)(66). Moreover, members of the miR-27 family of miRNAs, which contribute to the regulation of lipid metabolism, were recently reported to be increased by HCV and to contribute to liver steatosis (67,68).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus-Induced Upregulation of MicroRNA miR-146a-5p in Hepatocytes Promotes Viral Infection and Deregulates Metabolic Pathways Associated with Liver Disease Pathogenesis

Bandiera

Pernot

Saghire

et al. 2016

J Virol

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Hepatitis C virus (HCV)-induced chronic liver disease is a leading cause of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying HCC development following chronic HCV infection remain poorly understood. MicroRNAs (miRNAs) play an important role in homeostasis within the liver, and deregulation of miRNAs has been associated with liver disease, including HCC. While host miRNAs are essential for HCV replication, viral infection in turn appears to induce alterations of intrahepatic miRNA networks. Although the cross talk between HCV and liver cell miRNAs most likely contributes to liver disease pathogenesis, the functional involvement of miRNAs in HCV-driven hepatocyte injury and HCC remains elusive. Here we combined a hepatocyte-like cell-based model system, high-throughput small RNA sequencing, computational analysis, and functional studies to investigate HCV-miRNA interactions that may contribute to liver disease and HCC. Profiling analyses indicated that HCV infection differentially regulated the expression of 72 miRNAs by at least 2-fold, including miRNAs that were previously described to target genes associated with inflammation, fibrosis, and cancer development. Further investigation demonstrated that the miR-146a-5p level was consistently increased in HCV-infected hepatocyte-like cells and primary human hepatocytes, as well as in liver tissue from HCV-infected patients. Genomewide microarray and computational analyses indicated that miR-146a-5p overexpression modulates pathways that are related to liver disease and HCC development. Furthermore, we showed that miR-146a-5p has a positive impact on late steps of the viral replication cycle, thereby increasing HCV infection. Collectively, our data indicate that the HCV-induced increase in miR-146a-5p expression both promotes viral infection and is relevant for pathogenesis of liver disease. IMPORTANCEHCV is a leading cause of chronic liver disease and cancer. However, how HCV induces liver cancer remains poorly understood. There is accumulating evidence that a viral cure does not eliminate the risk for HCC development. Thus, there is an unmet medical need to develop novel approaches to predict and prevent virus-induced HCC. miRNA expression is known to be deregulated in liver disease and cancer. Furthermore, miRNAs are essential for HCV replication, and HCV infection alters miRNA expression. However, how miRNAs contribute to HCV-driven pathogenesis remains elusive. Here we show that HCV induces miRNAs that may contribute to liver injury and carcinogenesis. The miR-146a-5p level was consistently increased in different cell-based models of HCV infection and in HCV patient-derived liver tissue. Furthermore, miR-146a-5p increased HCV infection. Collectively, our data are relevant to understanding viral pathogenesis and may open perspectives for novel biomarkers and prevention of virus-induced liver disease and HCC. H epatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma (HCC) worldw...

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Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus-Induced Upregulation of MicroRNA miR-146a-5p in Hepatocytes Promotes Viral Infection and Deregulates Metabolic Pathways Associated with Liver Disease Pathogenesis

Bandiera

Pernot

Saghire

et al. 2016

J Virol

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“…Chronic ethanol feeding inhibits PPAR-α function due to the effect of acetaldehyde, which inhibits transcriptional activation of PPAR-α [91] . HCV causes down-regulation of PPAR-α [92] , and is able to inhibit its activity by inducing repression of PPAR-α signaling by micro RNA-27b [93] . Leptin, another fat-derived cytokine, may promote fibrogenesis through up-regulation of transforming growth factor-β [94] , but it also protects the liver from fat accumulation by lowering the expression of SREBP-1 [95] .…”

Section: Fat As An Endocrine Organ: Cytokinesmentioning

confidence: 99%

Liver steatosis in hepatitis C patients

González‐Reimers¹

2015

WJH

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would affect HCV patients who are also obese or diabetics. In fact, several genotypes exert metabolic effects which overlap with some of those observed in the metabolic syndrome. In this review we will analyse the pathogenic pathways involved in the development of steatosis in HCV patients. Several cytokines and adipokines also become activated and are involved in "pure" steatosic effects, in addition to inflammation. They are probably responsible for the evolution of simple steatosis to steatohepatitis, making it difficult to explain why such alterations only affect a proportion of steatosic patients. Core tip: Chronic hepatitis C virus (HCV) infection can lead to steatosis and steatohepatitis. Increased liver triglyceride synthesis is mediated by several transcription factors such as sterol regulatory elementbinding protein (SREBP) whose expression is enhanced, in turn, by HCV core protein. Chronic HCV infection is also associated with insulin resistance that seems to be selective because although it activates systemic lipolysis, it increases triglyceride synthesis within the liver. This is due to the stimulatory effect of insulin on SREBP. It remains to be answered why not all patients with HCV infection and steatosis develop steatohepatitis despite early cytokine activation and metabolic derangements. AbstractThere is controversy regarding some aspects of hepatitis C virus (HCV) infection-associated liver steatosis, and their relationship with body fat stores. It has classically been found that HCV, especially genotype 3, exerts direct metabolic effects which lead to liver steatosis. This supports the existence of a so called viral steatosis and a metabolic steatosis, which REVIEWSubmit a

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“…Typically, they repress target gene expression through effect on the mRNA stability or translation. To date, there is growing evidence and experimental studies which have specifically explored the involvement of miRNAs in the mechanism associated with NAFLD development by regulating corresponding genes [20,31]. For example, the results from our ongoing studies on potential gene targets using the target prediction algorithms and the pathway analysis tools have revealed that around 54 miRNAs regulate 107 genes involved in the pathogenesis of hepatic steatosis (unpublished data).…”

Section: General Progress Of Nafldmentioning

confidence: 94%

Molecular Regulation of Mirnas and Potential Biomarkers in the Progression of Hepatic Steatosis to NASH

et al. 2015

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Increasing evidence suggests that microRNAs regulate diverse biological functions in the liver and play a very important function in metabolic-related disorders such as nonalcoholic fatty liver disease via regulating their target genes expression. In this review, we summarized the most recent progress in identification of miRNAs involving in the progression of liver steatosis and discussed the possible mechanisms by which miRNAs contribute to the diverse pathogenic liver injuries. We provide insights into the functional network of miRNAs by connecting miRNAs, their targets and biological pathways associated to hepatic steatosis and fibrosis, with important implications for our understanding of phenotypic-based disease pathogenesis. We also discuss the possible roles and challenges of miRNAs as biomarkers for drug-induced liver injury.

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Hepatitis C virus induced up-regulation of microRNA-27: A novel mechanism for hepatic steatosis

Cited by 100 publications

References 44 publications

Hepatitis C Virus-Induced Upregulation of MicroRNA miR-146a-5p in Hepatocytes Promotes Viral Infection and Deregulates Metabolic Pathways Associated with Liver Disease Pathogenesis

Hepatitis C Virus-Induced Upregulation of MicroRNA miR-146a-5p in Hepatocytes Promotes Viral Infection and Deregulates Metabolic Pathways Associated with Liver Disease Pathogenesis

Liver steatosis in hepatitis C patients

Molecular Regulation of Mirnas and Potential Biomarkers in the Progression of Hepatic Steatosis to NASH

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