Differential expression of PTEN in hepatic tissue and hepatic stellate cells during rat liver fibrosis and its reversal

Zheng, Libo; Chen, Xiuli; Guo, Jinbo; Sun, Hui-Cong; Liu, Lei; Shih, David Q.; Zhang, Xiaolan

doi:10.3892/ijmm.2012.1151

Cited by 21 publications

(19 citation statements)

References 22 publications

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“…Decreased PTEN expression has been reported in fibrotic diseases of the lungs, heart, skin as well as liver [14–18]. Specifically, deletion of the Pten gene in mice results in excess deposition of type I collagen, while PTEN overexpression can reverse chemical-induced liver fibrosis [19].…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…A previous study showed that the expression of PTEN was decreased in rat fibrotic liver tissues and HSCs induced by bile duct ligation in vivo [ 12 ]. During the reversal of liver fibrosis, pretreated PTEN mRNA and protein expression normalized, showing the relationship between PTEN and the severity of rat hepatic fibrosis[ 13 ]. The study presented herein investigated the in vitro and in vivo effects of PTEN on liver fibrosis using adenoviral transduction of wild-type PTEN (Ad-PTEN), mutant PTEN (Ad-G129E), and PTEN short hairpin RNA (PTEN shRNA) to better characterize the molecular mechanisms of PTEN in liver fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Effects and mechanism of adenovirus-mediated phosphatase and tension homologue deleted on chromosome ten gene on collagen deposition in rat liver fibrosis

Xie

Zheng

et al. 2017

WJG

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AIMTo evaluate the effects of phosphatase and tension homologue deleted on chromosome ten (PTEN) gene on collagen metabolism in hepatic fibrosis and the underlying mechanisms.METHODSRat primary hepatic stellate cells (HSCs) and human LX-2 cells were transfected with adenovirus containing cDNA constructs encoding wild-type PTEN (Ad-PTEN), PTEN mutant G129E gene (Ad-G129E), and RNA interference constructs targeting the PTEN sequence PTEN short hairpin RNA to up-regulate and down-regulate the expression of PTEN. HSCs were assayed using fluorescent microscopy, real-time polymerase chain reaction, and western blotting. Moreover, a CCl4-induced rat hepatic fibrosis model was established to investigate the in vivo effects. Hematoxylin and eosin, and Masson’s trichrome were used to assess the histological changes. The expression of collagen I and III was assessed using immunohistochemistry and western blot analysis.RESULTSElevated expression of PTEN gene reduced serum levels of alanine transaminase and aspartate transaminase, decreased collagen deposition in the liver, and reduced hepatocyte necrosis. In contrast, knockdown of PTEN expression had an opposite effect, such as increased collagen deposition in the liver, and was molecularly characterized by the increased expression of matrix metalloproteinase (MMP)-13 (P < 0.01) and MMP-2 (P < 0.01), as well as decreased expression of the tissue inhibitor of metalloproteinase (TIMP)-1 (P < 0.01) and TIMP-2 (P < 0.01).CONCLUSIONThese data indicated that gene therapy using recombinant adenovirus encoding PTEN might be a novel way of treating hepatic fibrosis.

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“…As a chemical hepatotoxicant, CCL4 has been widely used for its reliability to induce liver fibrosis and cirrhosis in experiments [10,11], despite its high mortality rate (43.3%). This study demonstrates that CCL4 can also be used to induce hypersplenism.…”

Section: Discussionmentioning

confidence: 99%

Expression of M-CSF, TNF-β, IFN-γ, and IL-10 in Rats with Liver Cirrhosis and Hypersplenism and its Significance

Lv¹,

Deng²,

Yu³

et al. 2016

J Hypertens

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Objective: This study aimed to examine the expression of M-CSF, TNF-β, IFN-γ, and IL-10 in rats with liver cirrhosis and hypersplenism, and to investigate its significance.Methods: Seventy-two healthy male SD rats were randomly divided into a model group (n=60) and a control group (n=12). The rats in the model group were first gavaged with a 40% CCL4/peanut oil solution to develop cirrhosis and hypersplenism. The expression rates and intensities of the pro-inflammatory cytokines M-CSF, TNF-β, and IFN-γ, and the anti-inflammatory cytokine IL-10 in the spleen were measured and compared with the control group. The pro-inflammatory/anti-inflammatory cytokine ratio and its role were analyzed. Results:The positive expression rates of M-CSF, TNF-β, IFN-γ, and IL-10 in the model group (cirrhosis and hypersplenism) were 61.76%, 79.41%, 64.70%, and 88.24%, respectively, which were significantly different (P<0.05) from the 25%, 33.33%, 16.67%, and 50% in the control group. The relative protein expression intensities of M-CSF, TNF-β, IFN-γ, and IL-10 in the model group were 0.63 ± 0.58, 1.06 ± 0.49, 0.99 ± 0.38, and 1.12 ± 0.42, respectively, and were significantly different (P<0.05) from the 0.18 ± 0.12, 0.52 ± 0.27, 0.38 ± 0.28, and 0.60 ± 0.32 in the control group. The relative mRNA expression levels of M-CSF, TNF-β, IFN-γ, and IL-10 in the model group were 2.06 ± 0.11, 4.07 ± 0.19, 2.98 ± 0.11, and 7.94 ± 0.27, respectively, and were significantly different (P<0.05) from the 1.01 ± 0.05, 1.06 ± 0.11, 1.00 ± 0.31, and 1.02 ± 0.08 in the control group. Conclusion:The abnormally increased expression of M-CSF, TNF-β, IFN-γ, and IL-10 in rats with liver cirrhosis and hypersplenism, as well as the abnormal pro-inflammatory/anti-inflammatory cytokine ratio and regulation may play an important role in enhancing the phagocytosis of macrophages and causing peripheral cytopenias.

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Differential expression of PTEN in hepatic tissue and hepatic stellate cells during rat liver fibrosis and its reversal

Cited by 21 publications

References 22 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

Effects and mechanism of adenovirus-mediated phosphatase and tension homologue deleted on chromosome ten gene on collagen deposition in rat liver fibrosis

Expression of M-CSF, TNF-β, IFN-γ, and IL-10 in Rats with Liver Cirrhosis and Hypersplenism and its Significance

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