In Inflamed Intestinal Tissues and Epithelial Cells, Interleukin 22 Signaling Increases Expression of H19 Long Noncoding RNA, Which Promotes Mucosal Regeneration

Geng, Hua; Bu, Heng Fu; Liu, Fangyi; Wu, Longtao; Pfeifer, Karl; Chou, Pauline M.; Wang, Xiao; Sun, Jiaren; Lu, Lu; Pandey, Ashutosh Kumar; Bartolomei, Marisa S.; Plaen, Isabelle G. De; Wang, Peng; Yu, Jindan; Qian, Jiaming; Tan, Xiao Di

doi:10.1053/j.gastro.2018.03.058

Cited by 160 publications

(119 citation statements)

References 35 publications

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“…lncRNAs have essential biological functions, and H19 is one of the few well‐characterized lncRNAs, which is an imprinted and maternally expressed transcript . Aberrant expression of H19 has been associated with numerous disease conditions . The current study showed that BA patients had significantly higher levels of H19 mRNA in livers when compared to control subjects, which indicates that H19 may play a role in the pathogenesis of BA.…”

Section: Discussionsupporting

confidence: 51%

Long Noncoding RNA H19 Contributes to Cholangiocyte Proliferation and Cholestatic Liver Fibrosis in Biliary Atresia

et al. 2019

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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 (lncR-NAH19) 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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Section: Discussionsupporting

confidence: 51%

Long Noncoding RNA H19 Contributes to Cholangiocyte Proliferation and Cholestatic Liver Fibrosis in Biliary Atresia

et al. 2019

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“…5B and 5C), and it required STAT3. Previous study demonstrated IL-22 activates expression of lncRNA H19 in intestinal epithelial cells (IECs), which is required for IECs healing and regeneration [28]. In the current study, we hypothesize that IL-22 drives metabolic reprogramming to maintain mitochondrial fitness and treat liver injury through lncRNA H19.…”

Section: The Induction Of Lncrna H19 By Il-22 Activates Mtor Signalinmentioning

confidence: 76%

“…In the current study, we first demonstrated that IL-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness, which in turn regulated hepatocellular metabolic processes. Further data indicated that IL-22 was capable of upregulating lncRNA H19, AMPK, mTOR and AKT in hepatocytes, key regulators of cell proliferation and epithelial wound healing, to eliminate dysfunctional mitochondria and opening up a new arena for IL-22 mediated mechanisms of action [28,30]. Together, these data illustrated that the induction of metabolic reprogramming in hepatocytes could attribute to IL-22-mediated liver protective activities.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury

Chen

Zai

Fan

et al. 2020

Preprint

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AbstractInterleukin 22 (IL-22) is an epithelial survival cytokine that is at present being explored as therapeutic agents for acute and chronic liver injury. However, its molecular basis of protective activities remains poorly understood. Here we demonstrate that IL-22 inhibits the deteriorating metabolic states induced by stimuli in hepatocytes. Specifically, we provide evidence that IL-22 promotes oxidative phosphorylation (OXPHOS) and glycolysis and regulates the metabolic reprogramming related transcriptional responses. IL-22 controls metabolic regulators and enzymes activity through the induction of AMP-activated protein kinase (AMPK), AKT and mammalian target of rapamycin (mTOR), thereby ameliorating mitochondrial. The upstream effector lncRNA H19 also participates in the controlling of these metabolic processes in hepatocytes. Importantly, amelioration of liver injury by IL-22 through activation of metabolism relevant signaling and regulation of mitochondrial function are further demonstrated in cisplatin-induced liver injury and steatohepatitis. Collectively, our results reveal a novel mechanism underscoring the regulation of metabolic profiles of hepatocytes by IL-22 during liver injury, which might provide useful insights from the bench to the clinic in treating and preventing liver diseases.Graphical AbstractOur works demonstrate a critical role of IL-22 in regulating hepatocellular metabolism to treat liver injury via activating STAT3-lncRNA H19-AMPK-AKT-mTOR axis. These findings describe a novel mechanism underscoring the regulation of metabolic states of hepatocytes by IL-22 during liver injury with potentially broad therapeutic insights.

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“…This would allow for finer regulation of AQP3 expression by competing for miR‐874 and may also improve intestinal barrier dysfunction. Geng et al found that under normal conditions, H19 is transcriptionally silent in the small intestine of adult mice. However, it becomes strongly activated after LPS treatment.…”

Section: Introductionmentioning

confidence: 99%

“…Geng et al 20 shown that fasting for 48 hours inhibits small intestinal mucosal growth in mice. Importantly, Xiao et al 12 PRE1 has also previously been shown to regulate the expression of CCND1.…”

mentioning

confidence: 99%

Analysis of changes to lncRNAs and their target mRNAs in murine jejunum after radiation treatment

Gong

Wang

et al. 2018

J Cellular Molecular Medi

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LncRNAs have been reported to play an important role in various diseases. However, their role in the radiation‐induced intestinal injury is unknown. The goal of the present study was to analyse the potential mechanistic role of lncRNAs in the radiation‐induced intestinal injury. Mice were divided into two groups: Control (non‐irradiated) and irradiated. Irradiated mice were administered 14 Gy of abdominal irradiation (ABI) and were assessed 3.5 days after irradiation. Changes to the jejuna of ABI mice were analysed using RNA‐Seq for alterations to both lncRNA and mRNA. These results were validated using qRT‐PCR. LncRNAs targets were predicted based on analysis of lncRNAs‐miRNAs‐mRNAs interaction. 29 007 lncRNAs and 17 142 mRNAs were detected in the two groups. At 3.5 days post‐irradiation, 91 lncRNAs and 57 lncRNAs were significantly up‐ and downregulated respectively. Similarly, 752 mRNAs and 400 mRNAs were significantly up‐ and downregulated respectively. qRT‐PCR was used to verify the altered expression of four lncRNAs (ENSMUST00000173070, AK157361, AK083183, AK038898) and four mRNAs (Mboat1, Nek10, Ccl24, Cyp2c55). Gene ontology and KEGG pathway analyses indicated the predicted genes were mainly involved in the VEGF signalling pathway. This study reveals that the expression of lncRNAs was altered in the jejuna of mice post‐irradiation. Moreover, it provides a resource for the study of lncRNAs in the radiation‐induced intestinal injury.

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In Inflamed Intestinal Tissues and Epithelial Cells, Interleukin 22 Signaling Increases Expression of H19 Long Noncoding RNA, Which Promotes Mucosal Regeneration

Cited by 160 publications

References 35 publications

Long Noncoding RNA H19 Contributes to Cholangiocyte Proliferation and Cholestatic Liver Fibrosis in Biliary Atresia

Long Noncoding RNA H19 Contributes to Cholangiocyte Proliferation and Cholestatic Liver Fibrosis in Biliary Atresia

Interleukin-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury

Analysis of changes to lncRNAs and their target mRNAs in murine jejunum after radiation treatment

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