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Long noncoding RNA H19 - a new player in the pathogenesis of liver diseases.

ABSTRACT: The liver is a vital organ that controls glucose and lipid metabolism, hormone regulation, and bile secretion. Liver injury can occur from various insults such as viruses, metabolic diseases, and alcohol, which lead to acute and chronic liver diseases. Recent studies have demonstrated the implications of long noncoding RNAs (lncRNAs) in the pathogenesis of liver diseases. These newly discovered lncRNAs have various functions attributing to many cellular biological processes via distinct and diverse mechanisms. LncRNA H19, one of the first lncRNAs being identified, is highly expressed in fetal liver but not in adult normal liver. Its expression, however, is increased in liver diseases with various etiologies. In this review, we focused on the roles of H19 in the pathogenesis of liver diseases. This comprehensive review is aimed to provide useful perspectives and translational applications of H19 as a potential therapeutic target of liver diseases.

SUBMITTER: Yang Z

PROVIDER: S-EPMC9330166 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Long noncoding RNA H19 - a new player in the pathogenesis of liver diseases.

Yang Zhihong Z Zhang Ting T Han Sen S Kusumanchi Praveen P Huda Nazmul N Jiang Yanchao Y Liangpunsakul Suthat S

Translational research : the journal of laboratory and clinical medicine 20201120

The liver is a vital organ that controls glucose and lipid metabolism, hormone regulation, and bile secretion. Liver injury can occur from various insults such as viruses, metabolic diseases, and alcohol, which lead to acute and chronic liver diseases. Recent studies have demonstrated the implications of long noncoding RNAs (lncRNAs) in the pathogenesis of liver diseases. These newly discovered lncRNAs have various functions attributing to many cellular biological processes via distinct and dive ...[more]

PMID: 33227504

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Project description:BackgroundDevelopmental cardiac tissue holds remarkable capacity to regenerate after injury and consists of regenerative mononuclear diploid cardiomyocytes. On maturation, mononuclear diploid cardiomyocytes become binucleated or polyploid and exit the cell cycle. Cardiomyocyte metabolism undergoes a profound shift that coincides with cessation of regeneration in the postnatal heart. However, whether reprogramming metabolism promotes persistence of regenerative mononuclear diploid cardiomyocytes enhancing cardiac function and repair after injury is unknown. Here, we identify a novel role for RNA-binding protein LIN28a, a master regulator of cellular metabolism in cardiac repair after injury.MethodsLIN28a overexpression was tested using mouse transgenesis on postnatal cardiomyocyte numbers, cell cycle, and response to apical resection injury. With the use of neonatal and adult cell culture systems and adult and Mosaic Analysis with Double Markers myocardial injury models in mice, the effect of LIN28a overexpression on cardiomyocyte cell cycle and metabolism was tested. Last, isolated adult cardiomyocytes from LIN28a and wild-type mice 4 days after myocardial injury were used for RNA-immunoprecipitation sequencing.ResultsLIN28a was found to be active primarily during cardiac development and rapidly decreases after birth. LIN28a reintroduction at postnatal day (P) 1, P3, P5, and P7 decreased maturation-associated polyploidization, nucleation, and cell size, enhancing cardiomyocyte cell cycle activity in LIN28a transgenic pups compared with wild-type littermates. Moreover, LIN28a overexpression extended cardiomyocyte cell cycle activity beyond P7 concurrent with increased cardiac function 30 days after apical resection. In the adult heart, LIN28a overexpression attenuated cardiomyocyte apoptosis, enhanced cell cycle activity, cardiac function, and survival in mice 12 weeks after myocardial infarction compared with wild-type littermate controls. Instead, LIN28a small molecule inhibitor attenuated the proreparative effects of LIN28a on the heart. Neonatal rat ventricular myocytes overexpressing LIN28a mechanistically showed increased glycolysis, ATP production, and levels of metabolic enzymes compared with control. LIN28a immunoprecipitation followed by RNA-immunoprecipitation sequencing in cardiomyocytes isolated from LIN28a-overexpressing hearts after injury identified long noncoding RNA-H19 as its most significantly altered target. Ablation of long noncoding RNA-H19 blunted LIN28a-induced enhancement on cardiomyocyte metabolism and cell cycle activity.ConclusionsCollectively, LIN28a reprograms cardiomyocyte metabolism and promotes persistence of mononuclear diploid cardiomyocytes in the injured heart, enhancing proreparative processes, thereby linking cardiomyocyte metabolism to regulation of ploidy/nucleation and repair in the heart.

Project description:Cholestatic liver injury is an important clinical problem with limited understanding of disease pathologies. Exosomes are small extracellular vesicles released by a variety of cells, including cholangiocytes. Exosome-mediated cell-cell communication can modulate various cellular functions by transferring a variety of intracellular components to target cells. Our recent studies indicate that the long noncoding RNA (lncRNA), H19, is mainly expressed in cholangiocytes, and its aberrant expression is associated with significant down-regulation of small heterodimer partner (SHP) in hepatocytes and cholestatic liver injury in multidrug resistance 2 knockout (Mdr2-/- ) mice. However, how cholangiocyte-derived H19 suppresses SHP in hepatocytes remains unknown. Here, we report that cholangiocyte-derived exosomes mediate transfer of H19 into hepatocytes and promote cholestatic injury. Hepatic H19 level is correlated with severity of cholestatic injury in both fibrotic mouse models, including Mdr2-/- mice, a well-characterized model of primary sclerosing cholangitis (PSC), or CCl4 -induced cholestatic liver injury mouse models, and human PSC patients. Moreover, serum exosomal-H19 level is gradually up-regulated during disease progression in Mdr2-/- mice and patients with cirrhosis. H19-carrying exosomes from the primary cholangiocytes of wild-type (WT) mice suppress SHP expression in hepatocytes, but not the exosomes from the cholangiocytes of H19-/- mice. Furthermore, overexpression of H19 significantly suppressed SHP expression at both transcriptional and posttranscriptional levels. Importantly, transplant of H19-carrying serum exosomes of old fibrotic Mdr2-/- mice significantly promoted liver fibrosis (LF) in young Mdr2-/- mice. CONCLUSION:Cholangiocyte-derived exosomal-H19 plays a critical role in cholestatic liver injury. Serum exosomal H19 represents a noninvasive biomarker and potential therapeutic target for cholestatic diseases. (Hepatology 2018).

Project description:Activation of hepatic stellate cells (HSCs) represents the primary driving force to promote the progression of chronic cholestatic liver diseases. We previously reported that cholangiocyte-derived exosomal long noncoding RNA-H19 (lncRNA-H19) plays a critical role in promoting cholestatic liver injury. However, it remains unclear whether cholangiocyte-derived lncRNA-H19 regulates HSC activation, which is the major focus of this study. Both bile duct ligation (BDL) and Mdr2 knockout (Mdr2-/- ) mouse models were used. Wild-type and H19maternalΔExon1/+ (H19KO) mice were subjected to BDL. Mdr2-/- H19maternalΔExon1/+ (DKO) mice were generated. Exosomes isolated from cultured mouse and human cholangiocytes or mouse serum were used for in vivo transplantation and in vitro studies. Fluorescence-labeled exosomes and flow cytometry were used to monitor exosome uptake by hepatic cells. Collagen gel contraction and bromodeoxyuridine assays were used to determine the effect of exosomal-H19 on HSC activation and proliferation. Mouse and human primary sclerosing cholangitis (PSC)/primary biliary cholangitis (PBC) liver samples were analyzed by real-time PCR, western blot analysis, histology, and immunohistochemistry. The results demonstrated that hepatic H19 level was closely correlated with the severity of liver fibrosis in both mouse models and human patients with PSC and PBC. H19 deficiency significantly protected mice from liver fibrosis in BDL and Mdr2-/- mice. Transplanted cholangiocyte-derived H19-enriched exosomes were rapidly and preferentially taken up by HSCs and HSC-derived fibroblasts, and promoted liver fibrosis in BDL-H19KO mice and DKO mice. H19-enriched exosomes enhanced transdifferentiation of cultured mouse primary HSCs and promoted proliferation and matrix formation in HSC-derived fibroblasts. Conclusion: Cholangiocyte-derived exosomal H19 plays a critical role in the progression of cholestatic liver fibrosis by promoting HSC differentiation and activation and represents a potential diagnostic biomarker and therapeutic target for cholangiopathies.

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Long noncoding RNA H19 - a new player in the pathogenesis of liver diseases.

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Long noncoding RNA H19 - a new player in the pathogenesis of liver diseases.

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