The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Runping Liu - One of the best experts on this subject based on the ideXlab platform.
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long noncoding RNA H19 contributes to cholangiocyte proliferation and cholestatic liver fibrosis in biliary atresia
Hepatology, 2019Co-Authors: Yongtao Xiao, Runping Liu, Emily C Gurley, Phillip B Hylemon, Huiping Zhou, Wei CaiAbstract:Biliary atresia (BA) is a neonatal liver disease featuring cholestasis and severe liver fibrosis (LF). Despite advances in the development of surgical treatment, lacking an early diagnostic marker and intervention of LF invariably leads to death from end-stage liver disease in the early years of life. We previously reported that knockout of sphingosine 1-phosphate receptor 2 (S1PR2) protected mice from bile duct ligation (BDL)-induced cholangiocyte proliferation and LF. Our recent studies further showed that both hepatic and serum exosomal long noncoding RNA H19 (lncRNAH19) levels are correlated with cholestatic injury in multidrug resistance 2 knockout (Mdr2-/- ) mice. However, the role of lncRNAH19 in BA progression remains unclear. Here, we show that both hepatic and serum exosomal H19 levels are positively correlated with severity of fibrotic liver injuries in BA patients. H19 deficiency protects mice from BDL-induced cholangiocyte proliferation and LF by inhibiting bile-acid-induced expression and activation of S1PR2 and sphingosine kinase 2 (SphK2). Furthermore, H19 acts as a molecular sponge for members of the microRNA let-7 family, which results in up-regulation of high-mobility group AT-hook 2 (HMGA2), a known target of let-7 and enhancement of biliary proliferation. Conclusion: These results indicate that H19 plays a critical role in cholangiocyte proliferation and cholestatic liver injury in BA by regulating the S1PR2/SphK2 and let-7/HMGA2 axis. Serum exosomal H19 may represent a noninvasive diagnostic biomarker and potential therapeutic target for BA.
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cholangiocyte derived exosomal long noncoding RNA H19 promotes hepatic stellate cell activation and cholestatic liver fibrosis
Hepatology, 2019Co-Authors: Runping Liu, Emily C Gurley, Xuan Wang, Weiwei Zhu, Yanyan Wang, Derrick Zhao, Guang Liang, Weidong ChenAbstract: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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cholangiocyte derived exosomal long noncoding RNA H19 promotes cholestatic liver injury in mouse and humans
Hepatology, 2018Co-Authors: Runping Liu, Emily C Gurley, Zhiming Huang, Xuan Wang, Juan Wang, Hu Yang, Guanhua Lai, Luyong Zhang, Jasmohan S Bajaj, Melanie B WhiteAbstract: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 non-coding RNA 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. The hepatic H19 level is correlated with the severity of cholestatic injury in both fibrotic mouse models, including Mdr2−/− mice, a well-characterized model of primary sclerosing cholangitis (PSC), or carbon-tetrachloride (CCl4)-induced cholestatic liver injury mouse models, and human PSC patients. Moreover, serum exosomal-H19 level is gradually upregulated during disease progression in Mdr2−/− mice and cirrhotic patients. The 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 post-transcriptional levels. Importantly, transplant of H19-carrying serum exosomes of old fibrotic Mdr2−/− mice significantly promoted liver fibrosis in young Mdr2−/− mice. Conclusion Cholangiocyte-derived exosomal-H19 plays a critical role in cholestatic liver injury. Serum exosomal-H19 represents a novel non-invasive biomarker and potential therapeutic target for cholestatic diseases.
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the role of long noncoding RNA H19 in gender disparity of cholestatic liver injury in multidrug resistance 2 gene knockout mice
Hepatology, 2017Co-Authors: Runping Liu, Jing Yang, Luyong Zhang, Lixin Sun, Zhenzhou Jiang, Puneet Puri, Emily C GurleyAbstract:The multidrug resistance 2 knockout (Mdr2-/- ) mouse is a well-established model of cholestatic cholangiopathies. Female Mdr2-/- mice develop more severe hepatobiliary damage than male Mdr2-/- mice, which is correlated with a higher proportion of taurocholate in the bile. Although estrogen has been identified as an important player in intrahepatic cholestasis, the underlying molecular mechanisms of gender-based disparity of cholestatic injury remain unclear. The long noncoding RNA H19 is an imprinted, mateRNAlly expressed, and estrogen-targeted gene, which is significantly induced in human fibrotic/cirrhotic liver and bile duct-ligated mouse liver. However, whether aberrant expression of H19 accounts for gender-based disparity of cholestatic injury in Mdr2-/- mice remains unknown. The current study demonstrated that H19 was markedly induced (∼200-fold) in the livers of female Mdr2-/- mice at advanced stages of cholestasis (100 days old) but not in age-matched male Mdr2-/- mice. During the early stages of cholestasis, H19 expression was minimal. We further determined that hepatic H19 was mainly expressed in cholangiocytes, not hepatocytes. Both taurocholate and estrogen significantly activated the extracellular signal-regulated kinase 1/2 signaling pathway and induced H19 expression in cholangiocytes. Knocking down H19 not only significantly reduced taurocholate/estrogen-induced expression of fibrotic genes and sphingosine 1-phosphate receptor 2 in cholangiocytes but also markedly reduced cholestatic injury in female Mdr2-/- mice. Furthermore, expression of small heterodimer partner was substantially inhibited at advanced stages of liver fibrosis, which was reversed by H19 short hairpin RNA in female Mdr2-/- mice. Similar findings were obtained in human primary sclerosing cholangitis liver samples. Conclusion H19 plays a critical role in the disease progression of cholestasis and represents a key factor that causes the gender disparity of cholestatic liver injury in Mdr2-/- mice. (Hepatology 2017;66:869-884).
Emily C Gurley - One of the best experts on this subject based on the ideXlab platform.
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long noncoding RNA H19 contributes to cholangiocyte proliferation and cholestatic liver fibrosis in biliary atresia
Hepatology, 2019Co-Authors: Yongtao Xiao, Runping Liu, Emily C Gurley, Phillip B Hylemon, Huiping Zhou, Wei CaiAbstract:Biliary atresia (BA) is a neonatal liver disease featuring cholestasis and severe liver fibrosis (LF). Despite advances in the development of surgical treatment, lacking an early diagnostic marker and intervention of LF invariably leads to death from end-stage liver disease in the early years of life. We previously reported that knockout of sphingosine 1-phosphate receptor 2 (S1PR2) protected mice from bile duct ligation (BDL)-induced cholangiocyte proliferation and LF. Our recent studies further showed that both hepatic and serum exosomal long noncoding RNA H19 (lncRNAH19) levels are correlated with cholestatic injury in multidrug resistance 2 knockout (Mdr2-/- ) mice. However, the role of lncRNAH19 in BA progression remains unclear. Here, we show that both hepatic and serum exosomal H19 levels are positively correlated with severity of fibrotic liver injuries in BA patients. H19 deficiency protects mice from BDL-induced cholangiocyte proliferation and LF by inhibiting bile-acid-induced expression and activation of S1PR2 and sphingosine kinase 2 (SphK2). Furthermore, H19 acts as a molecular sponge for members of the microRNA let-7 family, which results in up-regulation of high-mobility group AT-hook 2 (HMGA2), a known target of let-7 and enhancement of biliary proliferation. Conclusion: These results indicate that H19 plays a critical role in cholangiocyte proliferation and cholestatic liver injury in BA by regulating the S1PR2/SphK2 and let-7/HMGA2 axis. Serum exosomal H19 may represent a noninvasive diagnostic biomarker and potential therapeutic target for BA.
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cholangiocyte derived exosomal long noncoding RNA H19 promotes hepatic stellate cell activation and cholestatic liver fibrosis
Hepatology, 2019Co-Authors: Runping Liu, Emily C Gurley, Xuan Wang, Weiwei Zhu, Yanyan Wang, Derrick Zhao, Guang Liang, Weidong ChenAbstract: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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cholangiocyte derived exosomal long noncoding RNA H19 promotes cholestatic liver injury in mouse and humans
Hepatology, 2018Co-Authors: Runping Liu, Emily C Gurley, Zhiming Huang, Xuan Wang, Juan Wang, Hu Yang, Guanhua Lai, Luyong Zhang, Jasmohan S Bajaj, Melanie B WhiteAbstract: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 non-coding RNA 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. The hepatic H19 level is correlated with the severity of cholestatic injury in both fibrotic mouse models, including Mdr2−/− mice, a well-characterized model of primary sclerosing cholangitis (PSC), or carbon-tetrachloride (CCl4)-induced cholestatic liver injury mouse models, and human PSC patients. Moreover, serum exosomal-H19 level is gradually upregulated during disease progression in Mdr2−/− mice and cirrhotic patients. The 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 post-transcriptional levels. Importantly, transplant of H19-carrying serum exosomes of old fibrotic Mdr2−/− mice significantly promoted liver fibrosis in young Mdr2−/− mice. Conclusion Cholangiocyte-derived exosomal-H19 plays a critical role in cholestatic liver injury. Serum exosomal-H19 represents a novel non-invasive biomarker and potential therapeutic target for cholestatic diseases.
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the role of long noncoding RNA H19 in gender disparity of cholestatic liver injury in multidrug resistance 2 gene knockout mice
Hepatology, 2017Co-Authors: Runping Liu, Jing Yang, Luyong Zhang, Lixin Sun, Zhenzhou Jiang, Puneet Puri, Emily C GurleyAbstract:The multidrug resistance 2 knockout (Mdr2-/- ) mouse is a well-established model of cholestatic cholangiopathies. Female Mdr2-/- mice develop more severe hepatobiliary damage than male Mdr2-/- mice, which is correlated with a higher proportion of taurocholate in the bile. Although estrogen has been identified as an important player in intrahepatic cholestasis, the underlying molecular mechanisms of gender-based disparity of cholestatic injury remain unclear. The long noncoding RNA H19 is an imprinted, mateRNAlly expressed, and estrogen-targeted gene, which is significantly induced in human fibrotic/cirrhotic liver and bile duct-ligated mouse liver. However, whether aberrant expression of H19 accounts for gender-based disparity of cholestatic injury in Mdr2-/- mice remains unknown. The current study demonstrated that H19 was markedly induced (∼200-fold) in the livers of female Mdr2-/- mice at advanced stages of cholestasis (100 days old) but not in age-matched male Mdr2-/- mice. During the early stages of cholestasis, H19 expression was minimal. We further determined that hepatic H19 was mainly expressed in cholangiocytes, not hepatocytes. Both taurocholate and estrogen significantly activated the extracellular signal-regulated kinase 1/2 signaling pathway and induced H19 expression in cholangiocytes. Knocking down H19 not only significantly reduced taurocholate/estrogen-induced expression of fibrotic genes and sphingosine 1-phosphate receptor 2 in cholangiocytes but also markedly reduced cholestatic injury in female Mdr2-/- mice. Furthermore, expression of small heterodimer partner was substantially inhibited at advanced stages of liver fibrosis, which was reversed by H19 short hairpin RNA in female Mdr2-/- mice. Similar findings were obtained in human primary sclerosing cholangitis liver samples. Conclusion H19 plays a critical role in the disease progression of cholestasis and represents a key factor that causes the gender disparity of cholestatic liver injury in Mdr2-/- mice. (Hepatology 2017;66:869-884).
Lingfei Jia - One of the best experts on this subject based on the ideXlab platform.
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long non coding RNA H19 inhibits adipocyte differentiation of bone marrow mesenchymal stem cells through epigenetic modulation of histone deacetylases
Scientific Reports, 2016Co-Authors: Yiping Huang, Yunfei Zheng, Chanyuan Jin, Lingfei JiaAbstract:Bone marrow mesenchymal stem cells (BMSCs) exhibit an increased propensity toward adipocyte differentiation accompanied by a reduction in osteogenesis in osteoporotic bone marrow. However, limited knowledge is available concerning the role of long non-coding RNAs (lncRNAs) in the differentiation of BMSCs into adipocytes. In this study, we demonstrated that lncRNA H19 and microRNA-675 (miR-675) derived from H19 were significantly downregulated in BMSCs that were differentiating into adipocytes. Overexpression of H19 and miR-675 inhibited adipogenesis, while knockdown of their endogenous expression accelerated adipogenic differentiation. Mechanistically, we found that miR-675 targeted the 3′ untranslated regions of the histone deacetylase (HDAC) 4–6 transcripts and resulted in deregulation of HDACs 4–6, essential molecules in adipogenesis. In turn, trichostatin A, an HDAC inhibitor, significantly reduced CCCTC-binding factor (CTCF) occupancy in the imprinting control region upstream of the H19 gene locus and subsequently downregulated the expression of H19. These results show that the CTCF/H19/miR-675/HDAC regulatory pathway plays an important role in the commitment of BMSCs into adipocytes.
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long noncoding RNA H19 promotes osteoblast differentiation via tgf β1 smad3 hdac signaling pathway by deriving mir 675
Stem Cells, 2015Co-Authors: Yiping Huang, Yunfei Zheng, Lingfei JiaAbstract:Long noncoding RNAs (lncRNAs) are emerging as important regulatory molecules at the transcriptional and post-transcriptional levels and may play essential roles in the differentiation of human bone marrow mesenchymal stem cell (hMSC). However, their roles and functions remain unclear. Here, we showed that lncRNA H19 was significantly upregulated after the induction of osteoblast differentiation. Overexpression of H19 promoted osteogenic differentiation of hMSCs in vitro and enhanced heterotopic bone formation in vivo, whereas knockdown of H19 inhibited these effects. Subsequently, we found that miR-675, encoded by exon1 of H19, promoted osteoblast differentiation of hMSCs and was partially responsible for the pro-osteogenic effect of H19. Investigating the underlying mechanism, we demonstrated that H19/miR-675 inhibited mRNA and protein expression of transforming growth factor-β1 (TGF-β1). The downregulation of TGF-β1 subsequently inhibited phosphorylation of Smad3. Meanwhile, H19/miR-675 downregulated the mRNA and protein levels of histone deacetylase (HDAC) 4/5, and thus increased osteoblast marker gene expression. Taken together, our results demonstrated that the novel pathway H19/miR-675/TGF-β1/Smad3/HDAC regulates osteogenic differentiation of hMSCs and may serve as a potential target for enhancing bone formation in vivo.
Xuan Wang - One of the best experts on this subject based on the ideXlab platform.
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cholangiocyte derived exosomal long noncoding RNA H19 promotes hepatic stellate cell activation and cholestatic liver fibrosis
Hepatology, 2019Co-Authors: Runping Liu, Emily C Gurley, Xuan Wang, Weiwei Zhu, Yanyan Wang, Derrick Zhao, Guang Liang, Weidong ChenAbstract: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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cholangiocyte derived exosomal long noncoding RNA H19 promotes cholestatic liver injury in mouse and humans
Hepatology, 2018Co-Authors: Runping Liu, Emily C Gurley, Zhiming Huang, Xuan Wang, Juan Wang, Hu Yang, Guanhua Lai, Luyong Zhang, Jasmohan S Bajaj, Melanie B WhiteAbstract: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 non-coding RNA 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. The hepatic H19 level is correlated with the severity of cholestatic injury in both fibrotic mouse models, including Mdr2−/− mice, a well-characterized model of primary sclerosing cholangitis (PSC), or carbon-tetrachloride (CCl4)-induced cholestatic liver injury mouse models, and human PSC patients. Moreover, serum exosomal-H19 level is gradually upregulated during disease progression in Mdr2−/− mice and cirrhotic patients. The 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 post-transcriptional levels. Importantly, transplant of H19-carrying serum exosomes of old fibrotic Mdr2−/− mice significantly promoted liver fibrosis in young Mdr2−/− mice. Conclusion Cholangiocyte-derived exosomal-H19 plays a critical role in cholestatic liver injury. Serum exosomal-H19 represents a novel non-invasive biomarker and potential therapeutic target for cholestatic diseases.
Melanie B White - One of the best experts on this subject based on the ideXlab platform.
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cholangiocyte derived exosomal long noncoding RNA H19 promotes cholestatic liver injury in mouse and humans
Hepatology, 2018Co-Authors: Runping Liu, Emily C Gurley, Zhiming Huang, Xuan Wang, Juan Wang, Hu Yang, Guanhua Lai, Luyong Zhang, Jasmohan S Bajaj, Melanie B WhiteAbstract: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 non-coding RNA 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. The hepatic H19 level is correlated with the severity of cholestatic injury in both fibrotic mouse models, including Mdr2−/− mice, a well-characterized model of primary sclerosing cholangitis (PSC), or carbon-tetrachloride (CCl4)-induced cholestatic liver injury mouse models, and human PSC patients. Moreover, serum exosomal-H19 level is gradually upregulated during disease progression in Mdr2−/− mice and cirrhotic patients. The 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 post-transcriptional levels. Importantly, transplant of H19-carrying serum exosomes of old fibrotic Mdr2−/− mice significantly promoted liver fibrosis in young Mdr2−/− mice. Conclusion Cholangiocyte-derived exosomal-H19 plays a critical role in cholestatic liver injury. Serum exosomal-H19 represents a novel non-invasive biomarker and potential therapeutic target for cholestatic diseases.
