Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKT pathway

Kumar, Pradeep; Raeman, Reben; Chopyk, Daniel M.; Smith, T. Lynn; Verma, Kiran; Liu, Yuying; Anania, Frank A.

doi:10.1016/j.bbadis.2018.08.012

Cited by 25 publications

(23 citation statements)

References 51 publications

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“…Decreased PTEN controlled by miRNAs in the liver is a mechanism of fibrogenesis. PI3K/AKT pathway is believed to regulate liver fibrosis,3233 Its upstream natural inhibitor PTEN exhibits a tumor suppressor role and is dysregulated in liver diseases 1934. PTEN has recently been identified as a target/biomarker for pharmacological therapy of liver fibrosis,35 and approaches to decrease PTEN expression would be promising strategies in liver injury 3436.…”

Section: Discussionmentioning

confidence: 99%

miR-140-3p Knockdown Suppresses Cell Proliferation and Fibrogenesis in Hepatic Stellate Cells via PTEN-Mediated AKT/mTOR Signaling

Huang

et al. 2019

Yonsei Med J

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Purpose Liver fibrosis is a major cause of morbidity and mortality and the outcome of various chronic liver diseases. Activation of hepatic stellate cells (HSCs) is the key event in liver fibrosis. Studies have confirmed that miR-140-3p plays a potential regulatory effect on HSC activation. However, whether miR-140-3p mediates the liver fibrosis remains unknown. Materials and Methods Expression of miR-140-3p was detected by real-time quantitative PCR (qPCR). Cell proliferation was measured by MTT, while cell apoptosis rate was determined via flow cytometry. Western blot assay was used to detect the expression of cleaved PARP. The fibrogenic effect was evaluated by expression of α-smooth muscle actin and desmin. Functional experiments were performed in transforming growth factor β1 (TGF-β1)-induced HSC-T6 cells with transfection of anti-miR-140-3p and/or siPTEN. Target binding between miR-140-3p and PTEN was predicted by the TargetScan database and identified using luciferase reporter assay and RNA immunoprecipitation. Results TGF-β1 induced the activation of HSC-T6 cells, and miR-140-3p expression varied according to HSC-T6 cell activation status. Knockdown of miR-140-3p reduced cell proliferation and the expressions of α-SMA and desmin, as well as increased apoptosis, in TGF-β1-induced HSC-T6 cells, which could be blocked by PTEN silencing. Additionally, inactivation of the AKT/mTOR signaling pathway stimulated by miR-140-3p knockdown was abolished when silencing PTEN expression. PTEN was negatively regulated by miR-140-3p via direct binding in HSC-T6 cells. Conclusion miR-140-3p is an important mediator in HSC-T6 cell activation, and miR-140-3p knockdown suppresses cell proliferation and fibrogenesis in TGF-β1-induced HSC-T6 cells, indicating that miR-140-3p may be a potential novel molecular target for liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

miR-140-3p Knockdown Suppresses Cell Proliferation and Fibrogenesis in Hepatic Stellate Cells via PTEN-Mediated AKT/mTOR Signaling

Huang

et al. 2019

Yonsei Med J

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“…There is a growing interest in epigenetic molecular mechanisms for investigations and therapeutic purpose. Aberrant DNMT expressions have been found in liver fibrosis conditions, 21 In conclusion, our study demonstrates that epigenetic silencing of LncRNA ANRIL regulates HSC activation though AMPK pathway is crucial pro-fibrogenic components forming an epigenetic cascade promoting liver fibrosis. This is a novel understanding of the role of DNMT3A and LncRNA ANRIL in HSC proliferation and the mechanism involved.…”

Section: Discussionmentioning

confidence: 55%

“…There is a growing interest in epigenetic molecular mechanisms for investigations and therapeutic purpose. Aberrant DNMT expressions have been found in liver fibrosis conditions, but the information regarding specific DNMT subtype involved in liver fibrosis is not appreciatively established. Accumulating evidence indicates the existence of cross regulation between DNA methylation and LncRNAs in the control of gene expression …”

Section: Discussionmentioning

confidence: 99%

Epigenetic silencing of LncRNA ANRIL enhances liver fibrosis and HSC activation through activating AMPK pathway

Yang

Zhang

et al. 2020

J Cellular Molecular Medi

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Long non‐coding RNAs (LncRNAs) and DNA methylation are important epigenetic mark play a key role in liver fibrosis. Currently, how DNA methylation and LncRNAs control the hepatic stellate cell (HSC) activation and fibrosis has not yet been fully characterized. Here, we explored the role of antisense non‐coding RNA in the INK4 locus (ANRIL) and DNA methylation in HSC activation and fibrosis. The expression levels of DNA methyltransferases 3A (DNMT3A), ANRIL, α‐Smooth muscle actin (α‐SMA), Type I collagen (Col1A1), adenosine monophosphate‐activated protein kinase (AMPK) and p‐AMPK in rat and human liver fibrosis were detected by immunohistochemistry, qRT‐PCR and Western blotting. Liver tissue histomorphology was examined by haematoxylin and eosin (H&E), Sirius red and Masson staining. HSC was transfected with DNMT3A‐siRNA, over‐expressing ANRIL and down‐regulating ANRIL. Moreover, cell proliferation ability was examined by CCK‐8, MTT and cell cycle assay. Here, our study demonstrated that ANRIL was significantly decreased in activated HSC and liver fibrosis tissues, while Col1A1, α‐SMA and DNMT3A were significantly increased in activated HSC and liver fibrosis tissues. Further, we found that down‐regulating DNMT3A expression leads to inhibition of HSC activation. Reduction in DNMT3A elevated ANRIL expression in activated HSC. Furthermore, we performed the over expression ANRIL suppresses HSC activation and AMPK signalling pathways. In sum, our study found that epigenetic DNMT3A silencing of ANRIL enhances liver fibrosis and HSC activation through activating AMPK pathway. Targeting epigenetic modulators DNMT3A and ANRIL, and offer a novel approach for liver fibrosis therapy.

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“…Recent studies showed that miR-29b could increase PTEN methylation via decreasing DNMT3b expression 15,16 . Next, we determined whether miR-29b was involved in regulating DNMT3b expression.…”

Section: Resultsmentioning

confidence: 99%

“…Adiponectin inhibits hepatic stellate cell activation via regulating PTEN expression. Mechanistically, upregulation of miR-29b induced by adiponectin can suppress DNMT3b transcription, leading to reduced PTEN methylation and ultimately suppressing the PI3K/AKT pathway 15 . HOTAIR, as a long intergenic non-coding RNA, downregulates miR-29b expression, leading to enhanced DNA methylation of PTEN promoter, which induces decreased PTEN expression 16 .…”

Section: Introductionmentioning

confidence: 99%

Di-n-butyl phthalate epigenetically induces reproductive toxicity via the PTEN/AKT pathway

Xing

et al. 2019

Cell Death Dis

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Di-n-butyl phthalate (DBP) is a kind of ubiquitous chemical linked to hormonal disruptions that affects male reproductive system. However, the mechanism of DBP-induced germ cells toxicity remains unclear. Here, we demonstrate that DBP induces reduction of proliferation, increase of apoptosis and DNA damage dependent on the PTEN/AKT pathway. Mechanistically, DBP decreases PTEN promoter methylation and increases its transcriptional activity, leading to increased PTEN expression. Notably, DNMT3b is confirmed as a target of miR-29b and miR-29b-mediated status of PTEN methylation is involved in the effects of DBP treatment. Meanwhile, DBP decreases AKT pathway expression via increasing PTEN expression. In addition, the fact that DBP decreases the sperm number and the percentage of motile and progressive sperm is associated with downregulated AKT pathway and sperm flagellum-related genes. Collectively, these findings indicate that DBP induces aberrant PTEN demethylation, leading to inhibition of the AKT pathway, which contributes to the reproductive toxicity.

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Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKT pathway

Cited by 25 publications

References 51 publications

miR-140-3p Knockdown Suppresses Cell Proliferation and Fibrogenesis in Hepatic Stellate Cells via PTEN-Mediated AKT/mTOR Signaling

miR-140-3p Knockdown Suppresses Cell Proliferation and Fibrogenesis in Hepatic Stellate Cells via PTEN-Mediated AKT/mTOR Signaling

Epigenetic silencing of LncRNA ANRIL enhances liver fibrosis and HSC activation through activating AMPK pathway

Di-n-butyl phthalate epigenetically induces reproductive toxicity via the PTEN/AKT pathway

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