Activation of Insulin-PI3K/Akt-p70S6K Pathway in Hepatic Stellate Cells Contributes to Fibrosis in Nonalcoholic Steatohepatitis

Cai, Cindy X.; Buddha, Hema; Castelino-Prabhu, Shobha; Zhang, Zhiwei; Britton, Robert S.; Bacon, Bruce R.; Neuschwander‐Tetri, Brent A.

doi:10.1007/s10620-017-4470-9

Cited by 58 publications

(42 citation statements)

References 60 publications

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“…4A; ~ > 2 fold change in sh-PTEN knockdown cells with or without TGFβ1 vs sh-pLKO.1 control). Since AKT phosphorylation is directly linked to cell survival and activation of α-SMA in HSCs [37–39]. We performed cell proliferation assays to determine whether knockdown of PTEN induced cell proliferation in LX-2 cells.…”

Section: Resultsmentioning

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: Resultsmentioning

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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“…In addition, GDF15 has been reported to induce phosphorylation of Akt and its downstream targets, c‐RAF and GSK‐3β . Insulin‐mediated activation of PI3K/Akt is also necessary for initial HSC activation . PI3K and ERK may in turn enhance SMAD binding under stressful conditions, via GDF15 secretion …”

Section: Discussionmentioning

confidence: 99%

Growth differentiation factor 15 predicts advanced fibrosis in biopsy‐proven non‐alcoholic fatty liver disease

Koo

Seo

et al. 2017

Liver International

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“…The decrease of phosphorylated Akt, ERK, and JNK in the miR-6133-treated LX-2 cells could be due to the downregulation of FGFR1 , a target gene of miR-6133-5p. Several reports have shown that Akt is involved in collagen synthesis and the activation of HSCs [ 4 , 5 ]. JNK has also been reported to regulate collagen synthesis and the activation of HSCs [ 6 , 7 , 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…Once activated, HSCs proliferate and differentiate into myofibroblasts and start to produce α-smooth muscle actin (α-SMA). Although extensive efforts have revealed that various signaling molecules such as Akt and c-Jun N-terminal kinase (JNK) control the activation and fibrogenesis of HSCs [ 4 , 5 , 6 , 7 , 8 ], the molecular processes involved in HSC activation are not entirely understood [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Effect of a Human MicroRNA, miR-6133-5p, on the Fibrotic Activity of Hepatic Stellate Cells in Culture

Hamada-Tsutsumi

Onishi

Matsuura

et al. 2020

IJMS

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Background: We recently identified 39 human microRNAs, which effectively suppress hepatitis B virus (HBV) replication in hepatocytes. Chronic HBV infection often results in active, hepatitis-related liver fibrosis; hence, we assessed whether any of these microRNAs have anti-fibrotic potential and predicted that miR-6133-5p may target several fibrosis-related genes. Methods: The hepatic stellate cell line LX-2 was transfected with an miR-6133-5p mimic and subsequently treated with Transforming growth factor (TGF)-β. The mRNA and protein products of the COL1A1 gene, encoding collagen, and the ACTA2 gene, an activation marker of hepatic stellate cells, were quantified. Results: The expression of COL1A1 and ACTA2 was markedly reduced in LX-2 cells treated with miR-6133-5p. Interestingly, phosphorylation of c-Jun N-terminal kinase (JNK) was also significantly decreased by miR-6133-5p treatment. The expression of several predicted target genes of miR-6133-5p, including TGFBR2 (which encodes Transforming Growth Factor Beta Receptor 2) and FGFR1 (which encodes Fibroblast Growth Factor Receptor 1), was also reduced in miR-6133-5p-treated cells. The knockdown of TGFBR2 by the corresponding small interfering RNA greatly suppressed the expression of COL1A1 and ACTA2. Treatment with the JNK inhibitor, SP600125, also suppressed COL1A1 and ACTA2 expression, indicating that TGFBR2 and JNK mediate the anti-fibrotic effect of miR-6133-5p. The downregulation of FGFR1 may result in a decrease of phosphorylated Akt, ERK (extracellular signal-regulated kinase), and JNK. Conclusion: miR-6133-5p has a strong anti-fibrotic effect, mediated by inactivation of TGFBR2, Akt, and JNK.

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Activation of Insulin-PI3K/Akt-p70S6K Pathway in Hepatic Stellate Cells Contributes to Fibrosis in Nonalcoholic Steatohepatitis

Cited by 58 publications

References 60 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

Growth differentiation factor 15 predicts advanced fibrosis in biopsy‐proven non‐alcoholic fatty liver disease

Inhibitory Effect of a Human MicroRNA, miR-6133-5p, on the Fibrotic Activity of Hepatic Stellate Cells in Culture

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