LncRNA-H19 induces hepatic stellate cell activation via upregulating alcohol dehydrogenase III-mediated retinoic acid signals

Wang, Zhimin; Xia, Siwei; Zhang, Tian; Wang, Zhenyi; Xiang, Yang; Kai, Jun; Cheng, Xudong; Tan, Shanzhong; Chen, Anping; Wang, Shijun; Zhang, Feng; Zhang, Zili; Zheng, Shizhong

doi:10.1016/j.intimp.2020.106470

Cited by 11 publications

(6 citation statements)

References 33 publications

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“…et al, 2020 ). More significantly, they confirmed that inhibition of ethanol dehydrogenase III (ADH3) completely abolished the effect of H19-mediated retinoic acid signaling, and that dihydroartemisinin (DHA), a natural inhibitor of H19, reduced both H19 and ADH3 expression and thus inhibited HSC activation ( Wang ZM. et al, 2020 ).…”

Section: The Regulatory Role Of Lncrnas In Liver Fibrosismentioning

confidence: 85%

“…Liu et al reported that cholangiocyte-derived exosomal H19 promotes cholestatic liver injury in Mdr2 −/− mice and promotes HSCs transdifferentiation and activation, along with upregulation of fibrotic gene expression in HSCs-derived fibroblasts ( Liu et al, 2019 ). Wang et al discovered that H19 can promote RARα and RXRβ mRNA and protein synthesis ( Wang ZM. et al, 2020 ), and its reduced expression reversed the extent of HSCs activation induced due to increased retinoic acid signaling.…”

Section: The Regulatory Role Of Lncrnas In Liver Fibrosismentioning

confidence: 99%

“…Meanwhile, it should be mentioned that H19 knockdown-mediated HSCs inactivation was inhibited by the activation of retinoic acid signaling. Furthermore, they demonstrated that H19 enhancement was positively associated with a synergistic increase in retinoic acid metabolism during HSCs activation ( Wang ZM. et al, 2020 ).…”

Section: The Regulatory Role Of Lncrnas In Liver Fibrosismentioning

confidence: 99%

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The Roles and Mechanisms of lncRNAs in Liver Fibrosis

et al. 2021

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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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Section: The Regulatory Role Of Lncrnas In Liver Fibrosismentioning

confidence: 85%

Section: The Regulatory Role Of Lncrnas In Liver Fibrosismentioning

confidence: 99%

Section: The Regulatory Role Of Lncrnas In Liver Fibrosismentioning

confidence: 99%

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The Roles and Mechanisms of lncRNAs in Liver Fibrosis

et al. 2021

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“…(22) Several studies have reported upregulation of H19 in different hepatic cells, cholestatic mouse models, and human patients with PSC, PBC, and BA. (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39) H19 not only functions as a sponge of miRNAs but also activates different signaling pathways involved in the activation of macrophages, cholangiocytes, and HSCs. Table 1 summarizes the key findings of the most recent studies which assessed the roles of H19 in different hepatic cells and cholestatic animal models.…”

Section: Lncrna H19 In Cholestatic Liver Diseasementioning

confidence: 99%

Long Noncoding RNA H19: A Key Player in Liver Diseases

2021

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“…Recently, the transformation of lipid droplets in HSCs has been extensively reported [ 3 , 4 ]. In healthy individuals, 80–90% of retinoids are stored in quiescent HSCs.…”

Section: Introductionmentioning

confidence: 99%

Cyp4a12-mediated retinol metabolism in stellate cells is the antihepatic fibrosis mechanism of the Chinese medicine Fuzheng Huayu recipe

Sun¹,

Peng

Ping

2023

Chin Med

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Background Hepatic stellate cells (HSCs), which contain multiple retinol-containing lipid droplets, are important profibrotic cells in liver fibrosis. Under Cyp4a12a/b oxidation, HSC activation was accompanied by the downregulation of genes involved in retinol metabolism, inducing RAE-1 production. By eliminating activated HSCs, NK cells expressing the activating receptor NKG2D are recruited to alleviate fibrosis. FZHY was found to significantly reduce the severity of liver fibrosis by inhibiting the activation and proliferation of HSCs. The molecular processes that govern retinol metabolism, on the other hand, are largely unexplored. This study focused on the regulation of Cyp4a12a/b by FZHY to elucidate the antifibrotic molecular mechanisms underlying the effect of FZHY on retinol metabolism. Methods To investigate mechanisms and altered pathways of FZHY against carbon tetrachloride (CCl4)-induced liver fibrosis based on transcriptomics data. Bioinformatics analysis was used to screen its pharmacological targets. The predicted targets were confirmed by a series of in vitro and in vivo experiments, including mass spectrometry, in situ hybridization, immunofluorescence assays and real-time PCR. Then, the results were further characterized by recombinant adenovirus vectors that were constructed and transfected into the cultured primary HSCs. Results Transcriptomics revealed that Cyp4a12a/b is nearly completely lost in liver fibrosis, and these effects might be partially reversed by FZHY therapy recovery. In vitro and in vivo studies indicated that Cyp4a12a/b deletion disrupted retinol metabolism and lowered Rae-1 expression. Activated HSCs successfully escape recognition and elimination by natural killer (NK) cells as a result of reduced Rae-1. Notablely, we discovered that FZHY may restore the Cyp4a12a/b capability, allowing the recovery of the cytotoxic function of NK cells against HSCs, and thereby reducing hepatic fibrosis by suppressing HSC activation. Conclusion Our findings revealed a new role for Cyp4a in retinol metabolism in the development of hepatic fibrosis, and they highlight Cyp4a12/Rae-1 signals as possible therapeutic targets for antifibrotic medicines.

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LncRNA-H19 induces hepatic stellate cell activation via upregulating alcohol dehydrogenase III-mediated retinoic acid signals

Cited by 11 publications

References 33 publications

The Roles and Mechanisms of lncRNAs in Liver Fibrosis

The Roles and Mechanisms of lncRNAs in Liver Fibrosis

Long Noncoding RNA H19: A Key Player in Liver Diseases

Cyp4a12-mediated retinol metabolism in stellate cells is the antihepatic fibrosis mechanism of the Chinese medicine Fuzheng Huayu recipe

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