Hepatic MiR-291b-3p Mediated Glucose Metabolism by Directly Targeting p65 to Upregulate PTEN Expression

Guo, Jun; Dou, Lin; Meng, Xiangyu; Chen, Zhenzhen; Yang, Weili; Fang, Weiwei; Yang, Chen; Huang, Xiuqing; Tang, Weiqing; Yang, Jichun; Li, Jian

doi:10.1038/srep39899

Cited by 18 publications

(16 citation statements)

References 38 publications

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“…Interestingly, miR291b was detected in both non-parenchymal cells and hepatocytes; treatment of mice with HA35 prevented these ethanol-induced increases in both cell types. While the increase in miR291b expression in non-parenchymal cells is consistent with our data from Kupffer cells after chronic ethanol feeding, induction of miR291b in hepatocytes may also be of pathophysiological significance, as miR291b-3p has been reported to induce hepatocyte apoptosis by downregulating HuR and Bcl-2 expression 28 and also impact glucose and lipid homeostasis in hepatocytes 29 , 30 . Therefore, future investigations will investigate if expression of miR291b in hepatocytes in response to ethanol exposure might play an important role in ethanol-induced hepatocyte injury.…”

Section: Discussionsupporting

confidence: 90%

Hyaluronic acid 35 normalizes TLR4 signaling in Kupffer cells from ethanol-fed rats via regulation of microRNA291b and its target Tollip

Saikia

Roychowdhury

Bellos

et al. 2017

Sci Rep

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TLR4 signaling in hepatic macrophages is increased after chronic ethanol feeding. Treatment of hepatic macrophages after chronic ethanol feeding with small-specific sized hyaluronic acid 35 (HA35) normalizes TLR4 signaling; however, the mechanisms for HA35 action are not completely understood. Here we used Next Generation Sequencing of microRNAs to identify negative regulators of TLR4 signaling reciprocally modulated by ethanol and HA35 in hepatic macrophages. Eleven microRNAs were up-regulated by ethanol; only 4 microRNAs, including miR291b, were decreased by HA35. Bioinformatics analysis identified Tollip, a negative regulator of TLR4, as a target of miR291b. Tollip expression was decreased in hepatic macrophages from ethanol-fed rats, but treatment with HA35 or transfection with a miR291b hairpin inhibitor restored Tollip expression and normalized TLR4-stimulated TNFα expression. In peripheral blood monocytes isolated from patients with alcoholic hepatitis, expression of TNFα mRNA was robustly increased in response to challenge with lipopolysaccharide. Importantly, pre-treatment with HA35 reduced TNFα expression by more than 50%. Taken together, we have identified miR291b as a critical miRNA up-regulated by ethanol. Normalization of the miR291b → Tollip pathway by HA35 ameliorated ethanol-induced sensitization of TLR4 signaling in macrophages/monocytes, suggesting that HA35 may be a novel therapeutic agent in the treatment of ALD.

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Section: Discussionsupporting

confidence: 90%

Hyaluronic acid 35 normalizes TLR4 signaling in Kupffer cells from ethanol-fed rats via regulation of microRNA291b and its target Tollip

Saikia

Roychowdhury

Bellos

et al. 2017

Sci Rep

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“…A previous study has indicated that miR-291-3p induces liver cell apoptosis via targeting RNA binding protein HuR (19). Additionally, increased miR-291-3p expression levels led to abnormal glucose and lipid metabolism in liver cells (20,21). These data suggested that abnormal miR-291-3p level in liver cells could result in liver cell damage.…”

Section: Introductionmentioning

confidence: 82%

miR‑219‑3p regulates the occurrence of hepatic fibrosis by targeting Smad2

Zhang

Zhu

et al. 2019

Exp Ther Med

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Abnormal expression of microRNA (miR)-219-3p has been widely identified in different tumors. However, whether miR-219-3p is involved in the progression of hepatic fibrosis (HF) has never been explored. The present study showed that compared with healthy controls, the levels of miR-291-3p in peripheral blood were decreased in patients with HF. Furthermore, much lower levels of miR-291-3p were identified in fibrotic liver tissues compared with that of normal liver tissues. Receiver operating characteristic curve analysis showed that the levels of miR-291-3p in peripheral blood may screen patients with HF from healthy controls. Reverse transcription quantitative polymerase chain reaction analysis showed that overexpression of miR-291-3p significantly suppressed the mRNA levels of Snai1, vascular endothelial-specific cadherin (VE-cadherin), Vimentin, transforming growth factor (TGF)-β1, and glial fibrillary acidic protein (GFAP). The protein levels of Snai1, VE-cadherin, Vimentin, TGF-β1, and GFAP were also decreased in hepatic stellate cells transfected with miR-291-3p mimics. Further study indicated that mothers against decapentaplegic homolog 2 (Smad2) was a target gene of miR-291-3p. More importantly, silencing of Smad2 could abolish miR-291-3p inhibition-induced TGF-β1 signaling activation. In summary, reduced peripheral blood miR-291-3p may be involved in the progression of HF via targeting Smad2.

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“…miRs are a cluster of small, non-coding RNAs. Numerous miRs have important roles in the regulation of the activation of the insulin signalling pathway, including miR-291b-3p (18), miR-200s (19), miR-152 (20), miR-20a-5p (21), miR-19a (22) and miR-301a (23). The results of our previous study suggested that miR-338-3p regulates the AKT/GSK pathway via targeting of PP4R1, which subsequently regulates protein phosphatase 4 (PP4) expression (11).…”

Section: Discussionmentioning

confidence: 99%

miR‑338‑3p mediates gluconeogenesis via targeting of PP4R1 in hepatocytes

Wang

Chen³

et al. 2018

Mol Med Report

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Hyperglycaemia is a characteristic of type 2 diabetes. In hepatocytes, impaired insulin sensitivity leads to increased gluconeogenesis and decreased glycogenesis. MicroRNA (miR)‑338‑3p is associated with tumour necrosis factor (TNF)‑α‑induced suppression of hepatic glycogenesis via regulation of protein phosphatase 4 regulatory subunit 1 (PP4R1). However, the effect of miR‑338‑3p on gluconeogenesis in hepatocytes remains unknown. In a previous study, it was demonstrated that miR‑338‑3p is downregulated in the livers of mice and in mouse HEPA1‑6 hepatocytes following treatment with TNF‑α. In the present study, the effect of miR‑338‑3p on TNF‑α‑induced gluconeogenesis in hepatocytes was investigated. The levels of phosphorylated‑FOXO1/FOXO1, phosphoenolpyruvate carboxykinase (PEPCK), peroxisome proliferator‑activated receptor γ coactivator (PGC‑1α) and glucose‑6‑phosphatase (G6Pase) were measured by western blotting. The mRNA levels of PEPCK, PGC‑1α and G6Pase were determined by quantitative polymerase chain reaction. Pyruvate tolerance testing was used to determine the gluconeogenesis of mouse livers. The results demonstrated that treatment with TNF‑α resulted in increased levels of gluconeogenesis in the livers of mice and decreased miR‑338‑3p expression levels in HEPA1‑6 cells. Overexpression of miR‑338‑3p reversed TNF‑α‑induced glucose production via enhancement of phosphorylated forkhead box O1 levels and downregulation of the expression levels of genes associated with gluconeogenesis, including peroxisome proliferator‑activated receptor γ coactivator‑1α, phosphoenolpyruvate carboxykinase and glucose‑6‑phosphatase. However, inhibition of miR‑338‑3p expression was revealed to enhance gluconeogenesis in the livers of mice and in HEPA1‑6 cells. Furthermore, downregulation of PP4R1 was revealed to attenuate the effect on glucose production following treatment with miR‑338‑3p inhibitors. In conclusion, the results of the present study revealed that miR‑338‑3p may be involved in TNF‑α‑mediated gluconeogenesis via targeting of PP4R1 in hepatocytes.

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Hepatic MiR-291b-3p Mediated Glucose Metabolism by Directly Targeting p65 to Upregulate PTEN Expression

Cited by 18 publications

References 38 publications

Hyaluronic acid 35 normalizes TLR4 signaling in Kupffer cells from ethanol-fed rats via regulation of microRNA291b and its target Tollip

Hyaluronic acid 35 normalizes TLR4 signaling in Kupffer cells from ethanol-fed rats via regulation of microRNA291b and its target Tollip

miR‑219‑3p regulates the occurrence of hepatic fibrosis by targeting Smad2

miR‑338‑3p mediates gluconeogenesis via targeting of PP4R1 in hepatocytes

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