Inhibition of SIRT2 suppresses hepatic fibrosis

Arteaga, Maribel; Shang, Na; Ding, Xianzhong; Yong, Sherri; Cotler, Scott J.; Denning, Mitchell F.; Shimamura, Takashi; Breslin, Peter; Lüscher, Bernhard; Qiu, Wei

doi:10.1152/ajpgi.00271.2015

Cited by 38 publications

(44 citation statements)

References 40 publications

(46 reference statements)

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“…Since PDGFR-α is one of the most important factors that promotes HSC activation via the augmentation of TGF-β signaling, HSC survival and proliferation [40, 41], inhibition of PDGFR-α is probably an important mechanism by which SIRT1 attenuates HSC activation and liver fibrosis. Second, c-Myc is known to promote HSC activation and proliferation [32]. Our data showed that overexpression of SIRT1 markedly decreased expression of c-Myc in cultured HSCs, suggesting that SIRT1 inhibits HSC activation via the downregulation of c-Myc.…”

Section: Discussionmentioning

confidence: 67%

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Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression

Ramírez

Yin

et al. 2017

Journal of Hepatology

136

119

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Background and Aims Aging is known to exacerbate the progression of alcoholic liver disease (ALD), but the underlying mechanisms remain obscure. Methods C57BL/6 mice were subjected to short-term (10-days) ethanol-plus-one binge or long- term (8-weeks) ethanol-plus-multiple binges of ethanol. Liver injury and fibrosis were determined. Hepatic stellate cells (HSCs) were isolated and used in in vitro studies. Results Compared to young (8–12 weeks) mice, middle-aged (12–14 months) and old (>16 months) mice were more susceptible to liver injury, inflammation, and oxidative stress induced by short-term-plus-one binge or long-term-plus-multiple binges of ethanol feeding. Long-term-plus- multiple binges of ethanol feeding induced greater liver fibrosis in middle-aged mice than that in young mice. Hepatic expression of Sirtuin 1 (SIRT1) protein was downregulated in the middle-aged mice compared to young mice. Restoration of SIRT1 expression via the administration of adenovirus-SIRT1 vector ameliorated short-term-plus-binge ethanol-induced liver injury and fibrosis in middle-aged mice. HSCs isolated from middle-aged mice expressed lower levels of SIRT1 protein and were more susceptible to spontaneous activation in in vitro culture than those from young mice. Overexpression of SIRT1 reduced activation of HSCs from middle-aged mice in vitro with downregulation of PDGFR-α and c-Myc, while deletion of SIRT1 activated HSCs isolated from young mice in vitro. Finally, HSC-specific SIRT1 knockout mice were more susceptible to short-term-plus-binge ethanol-induced liver fibrosis with upregulation of PDGFR-α expression. Conclusions Aging exacerbates ALD in mice through the downregulation of SIRT1 in hepatocytes and HSCs. Activation of SIRT1 may serve as a novel target for the treatment of ALD.

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Section: Discussionmentioning

confidence: 67%

“…To further examine the mechanism by which SIRT1 inhibits HSC activation, we examined the expression of c-Myc that is known as an important onco-protein to promote HSC activation [32]. As illustrated in Fig.…”

Section: Resultsmentioning

confidence: 99%

Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression

Ramírez

Yin

et al. 2017

Journal of Hepatology

136

119

View full text Add to dashboard Cite

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“…Inhibition of the SIRT2 pathway is also anti-fibrotic. A previous study revealed that SIRT2 promoted hepatic fibrosis and SIRT2 inhibition suppressed hepatic fibrogenesis [10]. Jung et al [33] found that SIRT2 regulated CXCL2 and CCL2 expression in lipopolysaccharide (LPS)-induced renal tubular cells injury, and SIRT2 regulation may exhibit beneficial effects in renal inflammatory injury.…”

Section: Discussionmentioning

confidence: 99%

“…The inflammatory cells secrete many proinflammatory and profibrotic cytokines, including transforming growth factor-β1 (TGF-β1), which is involved in excessive ECM accumulation and TIF progression [9]. A previous study suggested that SIRT2 promoted hepatic fibrosis, and SIRT2 inhibition attenuated the development of hepatic fibrogenesis [10]. Another study demonstrated that non-specific blockade of the SIRT1/2 pathway attenuated renal fibrosis [11].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of SIRT2 Alleviates Fibroblast Activation and Renal Tubulointerstitial Fibrosis via MDM2

You

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Renal tubular epithelial cells and fibroblasts are the main sources of myofibroblasts, and these cells produce the extracellular matrix during tubulointerstitial fibrosis (TIF). Histone deacetylases (HDAC) inhibitors exert an antifibrogenic effect in the skin, liver and lung. Sirtuin 2 (SIRT2), which is a class III HDAC, is an important member of NAD⁺-dependent protein deacetylases. The current study evaluated the role of SIRT2 in renal TIF. Methods: Immunohistochemical staining and Western blot were performed to evaluate SIRT2 expression in TIF patients and unilateral urethral obstruction (UUO) mice. Western blot was used to assess the protein levels of SIRT2, α-SMA, collagen III, fibronectin, and MDM2 in tubular epithelial cells and fibroblasts. The specific inhibitor AGK2 was used to inhibit SIRT2 activity, and targeted siRNA was used to suppress SIRT2 expression. Results: SIRT2 expression increased in the tubulointerstitium of TIF patients and UUO mice. SIRT2 inhibition ameliorated TIF in UUO mice. SIRT2 expression in tubular cells was unchanged after exposure to TGF-β1. The SIRT2-specifc inhibitor AGK2 did not attenuate TGF-β1-induced tubular epithelial-mesenchymal transition. However, SIRT2 was upregulated in fibroblasts, and fibroblasts were activated after TGF-β1 treatment. Genetic knockdown and chemical inhibition of SIRT2 attenuated TGF-β1-induced fibroblast activation. We also explored the downstream signaling of SIRT2 during fibroblast activation. Genetic knockdown and chemical inhibition of SIRT2 suppressed TGF-β1-induced increase in MDM2 expression, and inhibition of the MDM2-p53 interaction using Nutlin-3 did not suppress SIRT2 upregulation. Conclusion: Our results suggest that SIRT2 participates in the activation of fibroblasts and TIF, which is mediated via regulation of the MDM2 pathway, and the downregulation of SIRT2 may be a therapeutic strategy for renal fibrosis.

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“…Lentiviral pLKO.1 plasmids for shIGF1R (Table 1) or scrambled shRNA (SHC002; Sigma‐Aldrich) were packaged with the cytomegalovirus plasmid (pCMV)‐dr8.2 (Addgene) and pCMV‐VSVG (Addgene) in 293T cells to produce lentiviral particles as described 19, 20…”

Section: Methodsmentioning

confidence: 99%

Inhibition of insulin‐like growth factor 1 receptor enhances the efficacy of sorafenib in inhibiting hepatocellular carcinoma cell growth and survival

Wang

Bank

Malnassy

et al. 2018

Hepatology Communications

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Hepatocellular carcinoma (HCC) is the fifth most common primary cancer and second largest cause of cancer‐related death worldwide. The first‐line oral chemotherapeutic agent sorafenib only increases survival in patients with advanced HCC by less than 3 months. Most patients with advanced HCC have shown limited response rates and survival benefits with sorafenib. Although sorafenib is an inhibitor of multiple kinases, including serine/threonine‐protein kinase c‐Raf, serine/threonine‐protein kinase B‐Raf, vascular endothelial growth factor receptor (VEGFR)‐1, VEGFR‐2, VEGFR‐3, and platelet‐derived growth factor receptor β, HCC cells are able to escape from sorafenib treatment using other pathways that the drug insufficiently inhibits. The aim of this study was to identify and target survival and proliferation pathways that enable HCC to escape the antitumor activity of sorafenib. We found that insulin‐like growth factor 1 receptor (IGF1R) remains activated in HCC cells treated with sorafenib. Knockdown of IGF1R sensitizes HCC cells to sorafenib treatment and decreases protein kinase B (AKT) activation. Overexpression of constitutively activated AKT reverses the effect of knockdown of IGF1R in sensitizing HCC cells to treatment with sorafenib. Further, we found that ceritinib, a drug approved by the U.S. Food and Drug Administration for treatment of non‐small cell lung cancer, effectively inhibits the IGF1R/AKT pathway and enhances the inhibitory efficacy of sorafenib in human HCC cell growth and survival in vitro, in a xenograft mouse model and in the c‐Met/β‐catenin‐driven HCC mouse model. Conclusion: Our study provides a biochemical basis for evaluation of a new combination treatment that includes IGF1R inhibitors, such as ceritinib and sorafenib, in patients with HCC. (Hepatology Communications 2018;2:732‐746)

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Inhibition of SIRT2 suppresses hepatic fibrosis

Cited by 38 publications

References 40 publications

Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression

Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression

Inhibition of SIRT2 Alleviates Fibroblast Activation and Renal Tubulointerstitial Fibrosis via MDM2

Inhibition of insulin‐like growth factor 1 receptor enhances the efficacy of sorafenib in inhibiting hepatocellular carcinoma cell growth and survival

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