The let-7/Lin28 axis regulates activation of hepatic stellate cells in alcoholic liver injury

McDaniel, Kelly; Huang, Li; Sato, Keisaku; Wu, Nan; Annable, Tami; Zhou, Tianhao; Ramos‐Lorenzo, Sugeily; Wan, Ying; Huang, Qiaobing; Francis, Heather; Glaser, Shannon; Tsukamoto, Hidekazu; Alpini, Gianfranco; Meng, Fanyin

doi:10.1074/jbc.m116.773291

Cited by 59 publications

(55 citation statements)

References 32 publications

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“…Recently published studies have clarified the role of miRNAs in liver fibrosis [29,30,44]. Not surprisingly, miRNAs have been shown to play both an anti-fibrogenic and a profibrogenic role depending on the genes targeted and the nature of the stimulus [20–22,31,32].…”

Section: Discussionmentioning

confidence: 99%

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

Kumar¹,

Raeman²,

Chopyk³

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Adiponectin inhibits hepatic stellate cell (HSC) activation and subsequent development of liver fibrosis via multiple mechanisms. Phosphatase and tensin homolog deletion 10 (PTEN) plays a crucial role in suppression of HSC activation, but its regulation by adiponectin is not fully understood. Here, we investigated the effect of adiponectin on PTEN in LX-2 cells, a human cell line and examined the underlying molecular mechanisms involved in adiponectin-mediated upregulation of PTEN activity during fibrosis. PTEN expression was found to be significantly reduced in the livers of mice treated with CCl4, whereas its expression was rescued by adiponectin treatment. The DNA methylation proteins DNMT1, DNMT3A, and DNMT3B are all highly expressed in activated primary HSCs compared to quiescent HSCs, and thus represent additional regulatory targets during liver fibrogenesis. Expression of DNMT proteins was significantly induced in the presence of fibrotic stimuli; however, only DNMT3B expression was reduced in the presence of adiponectin. Adiponectin-induced suppression of DNMT3B was found to be mediated by enhanced miR-29b expression. Furthermore, PTEN expression was significantly increased by overexpression of miR-29b, whereas its expression was markedly reduced by a miR-29b inhibitor in LX-2 cells. These findings suggest that adiponectin-induced upregulation of miR-29b can suppress DNMT3B transcription in LX-2 cells, thus resulting in reduced methylation of PTEN CpG islands and ultimately suppressing the PI3K/AKT pathway. Together, these data suggest a possible new explanation for the inhibitory effect of adiponectin on HSC activation and liver fibrogenesis.

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Section: Discussionmentioning

confidence: 99%

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

Kumar¹,

Raeman²,

Chopyk³

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Up to 90% of circulating miRNAs are associated with proteins, and different miRNAs were enriched in specific extracellular compartments (e.g., let‐7a was predominant in the vesicle‐rich fractions in healthy individuals). We have demonstrated that let‐7 regulates liver inflammation and fibrosis through lin28 . In PSC models we have alternatively shown that an increase of let‐7, by repression of Lin28, improved fibrosis after alcoholic liver injury and decreased tissue inhibitor of metalloproteinase 3 levels.…”

Section: Discussionmentioning

confidence: 87%

“…(10) We have previously shown that suppression of Lin28 homolog, a downstream target of let-7, increases let-7 and mitigates progression of alcoholic liver disease. (11) Additionally, we have shown that increased let-7 expression as a result of suppression of secretin ameliorated cholestatic liver injury. (10) Let-7, as well as other miRNAs, could be transmitted from stem cells to damaged cells through extracellular vesicles (EVs) to repair or ameliorate damage during liver repair through their downstream targets.…”

mentioning

confidence: 91%

“…The miRNA let‐7 is reduced in MDR2 ‐/‐ mice, PSC patients, and cholestatic liver patients . We have previously shown that suppression of Lin28 homolog, a downstream target of let‐7, increases let‐7 and mitigates progression of alcoholic liver disease . Additionally, we have shown that increased let‐7 expression as a result of suppression of secretin ameliorated cholestatic liver injury .…”

mentioning

confidence: 93%

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Amelioration of Ductular Reaction by Stem Cell Derived Extracellular Vesicles in MDR2 Knockout Mice via Lethal‐7 microRNA

McDaniel

Wu²,

Zhou

et al. 2019

Hepatology

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Cholangiopathies are diseases that affect cholangiocytes, the cells lining the biliary tract. Liver stem cells (LSCs) are able to differentiate into all cells of the liver and possibly influence the surrounding liver tissue by secretion of signaling molecules. One way in which cells can interact is through secretion of extracellular vesicles (EVs), which are small membrane‐bound vesicles that contain proteins, microRNAs (miRNAs), and cytokines. We evaluated the contents of liver stem cell–derived EVs (LSCEVs), compared their miRNA contents to those of EVs isolated from hepatocytes, and evaluated the downstream targets of these miRNAs. We finally evaluated the crosstalk among LSCs, cholangiocytes, and human hepatic stellate cells (HSCs). We showed that LSCEVs were able to reduce ductular reaction and biliary fibrosis in multidrug resistance protein 2 (MDR2)‐/‐ mice. Additionally, we showed that cholangiocyte growth was reduced and HSCs were deactivated in LSCEV‐treated mice. Evaluation of LSCEV contents compared with EVs derived from hepatocytes showed a large increase in the miRNA, lethal‐7 (let‐7). Further evaluation of let‐7 in MDR2‐/‐ mice and human primary sclerosing cholangitis samples showed reduced levels of let‐7 compared with controls. In liver tissues and isolated cholangiocytes, downstream targets of let‐7 (identified by ingenuity pathway analysis), Lin28a (Lin28 homolog A), Lin28b (Lin28 homolog B), IL‐13 (interleukin 13), NR1H4 (nuclear receptor subfamily 1 group H member 4) and NF‐κB (nuclear factor kappa B), are elevated in MDR2‐/‐ mice, but treatment with LSCEVs reduced levels of these mediators of ductular reaction and biliary fibrosis through the inhibition of NF‐κB and IL‐13 signaling pathways. Evaluation of crosstalk using cholangiocyte supernatants from LSCEV‐treated cells on cultured HSCs showed that HSCs had reduced levels of fibrosis and increased senescence. Conclusion: Our studies indicate that LSCEVs could be a possible treatment for cholangiopathies or could be used for target validation for future therapies.

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“…The disruption in Let‐7 and LIN28/28B ratio leads to oncogenesis. These data provide novel insights into molecular mechanisms and argue for new therapeutic approaches for human alcoholic liver fibrosis (McDaniel et al, ).…”

Section: Roles Of Mi‐rnas In Aldmentioning

confidence: 99%

Noncoding RNAs in alcoholic liver disease

Chen

et al. 2019

Journal Cellular Physiology

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Alcoholic liver disease (ALD) is a complex process with high morbitity and can cause liver dysfunction, which contains a wide spectrum of hepatic lesions, including steatohepatitis, fibrosis, cirrhosis, and eventually hepatocellular carcinoma. To date, the molecular mechanisms for ALD have not been fully explored and an effective therapy is still missing. Overwhelming evidence shows dysregulation of noncoding RNAs (ncRNAs), particularly microRNAs (miRNAs), is correlated with etiopathogenesis and progress of ALD including hepatocyte damage, disrupted lipid metabolism, aggressive inflammatory responses, oxidative stress, programmed cell death, fibrosis, and epigenetic changes induced by alcohol. For example, circulating miRNA‐122 is a marker of hepatocyte damage, and miRNA‐155 is a potential marker of inflammation, indicating their diagnosis therapeutic potential in ALD. In addition, roles for long noncoding RNAs (lncRNAs) and circular RNAs in ALD are being uncovered. Further, circulating ncRNAs and exosome‐derived ncRNAs have attracted more attention lately, suggesting a role in the prevention and treatment of ALD. This review covers the roles of ncRNAs in ALD, and the potential uses as markers for diagnosis and therapeutic options.

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The let-7/Lin28 axis regulates activation of hepatic stellate cells in alcoholic liver injury

Cited by 59 publications

References 32 publications

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

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

Amelioration of Ductular Reaction by Stem Cell Derived Extracellular Vesicles in MDR2 Knockout Mice via Lethal‐7 microRNA

Noncoding RNAs in alcoholic liver disease

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