A Redox-resistant Sirtuin-1 Mutant Protects against Hepatic Metabolic and Oxidant Stress

Шао, Ди; Fry, Jessica; Han, Jing‐Yan; Hou, Xiuyun; Pimentel, David R.; Matsui, Reiko; Cohen, Richard A.; Bachschmid, Markus

doi:10.1074/jbc.m113.520403

Cited by 62 publications

(78 citation statements)

References 71 publications

(85 reference statements)

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“…We have previously shown that metabolic or nitrosative stress increases SirT1 reversible oxidative modification, which inhibits its enzyme activity and promotes hepatocyte apoptosis (67). Consistent with these findings, here we demonstrated that Glrx deficiency decreases SirT1 activity by GSH adducts and consequently increases acetylation of Srebp1 and expression of lipid synthesis genes, including Fasn and Scd1 in the liver (Fig.…”

Section: Glrxsupporting

confidence: 79%

“…Activation of SirT1 improved NAFL and conversely hepatic SirT1 deficiency led to steatosis (56). Inhibition of SirT1 activity by reversible GSH adducts has recently been described by our group and was confirmed by other investigators (11,67,71,77). Because NAFL (58) is associated with oxidative stress, increased protein GSH adducts may play an important role in the pathogenesis of steatotic livers.…”

Section: Introductionsupporting

confidence: 56%

“…Under oxidative and metabolic stress, mutant SirT1 maintains full activity and exhibits no reversible oxidative modifications (67). Overexpression of the mutant SirT1, as compared with WT, markedly attenuated lipid accumulation-triglycerides and cholesterol-in HepG2 cells under HPHG treatment and Glrx ablation (Fig.…”

Section: Fig 3 Glrx Repletion In Glrxmentioning

confidence: 99%

“…Our previous study (67) showed that HFD induced metabolic syndrome in mice and increased reversible cysteine oxidation of proteins in the liver. To determine whether elevated oxidative cysteine modifications caused by HFD can…”

Section: Glrx Deficiency Accelerates Diet-induced Naflmentioning

confidence: 99%

“…SirT1, an NAD + -dependent class III histone deacetylase, has emerged as a central regulator of hepatic lipid metabolism (46,60,63,67,75), and we have recently described it can be modified by GSH adducts (67).…”

Section: Glrx Deficiency Induces Hepatic Steatosis Through Inhibitionmentioning

confidence: 99%

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Glutaredoxin-1 Deficiency Causes Fatty Liver and Dyslipidemia by Inhibiting Sirtuin-1

Шао

Han

Hou

et al. 2017

Antioxidants & Redox Signaling

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Aims: Nonalcoholic fatty liver (NAFL) is a common liver disease associated with metabolic syndrome, obesity, and diabetes that is rising in prevalence worldwide. Various molecular perturbations of key regulators and enzymes in hepatic lipid metabolism cause NAFL. However, redox regulation through glutathione (GSH) adducts in NAFL remains largely elusive. Glutaredoxin-1 (Glrx) is a small thioltransferase that removes protein GSH adducts without having direct antioxidant properties. The liver contains abundant Glrx but its metabolic function is unknown. Results: Here we report that normal diet-fed Glrx-deficient mice (Glrx -/-) spontaneously develop obesity, hyperlipidemia, and hepatic steatosis by 8 months of age. Adenoviral Glrx repletion in the liver of Glrx -/-mice corrected lipid metabolism. Glrx -/-mice exhibited decreased sirtuin-1 (SirT1) activity that leads to hyperacetylation and activation of SREBP-1 and upregulation of key hepatic enzymes involved in lipid synthesis. We found that GSH adducts inhibited SirT1 activity in Glrx -/-mice. Hepatic expression of nonoxidizable cysteine mutant SirT1 corrected hepatic lipids in Glrx -/-mice. Wild-type mice fed high-fat diet develop metabolic syndrome, diabetes, and NAFL within several months. Glrx deficiency accelerated high-fat-induced NAFL and progression to steatohepatitis, manifested by hepatic damage and inflammation. Innovation: These data suggest an essential role of hepatic Glrx in regulating SirT1, which controls protein glutathione adducts in the pathogenesis of hepatic steatosis. Conclusion: We provide a novel redox-dependent mechanism for regulation of hepatic lipid metabolism, and propose that upregulation of hepatic Glrx may be a beneficial strategy for NAFL. Antioxid. Redox Signal. 27, 313-327.

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Section: Glrxsupporting

confidence: 79%

Section: Introductionsupporting

confidence: 56%

Section: Fig 3 Glrx Repletion In Glrxmentioning

confidence: 99%

Section: Glrx Deficiency Accelerates Diet-induced Naflmentioning

confidence: 99%

Section: Glrx Deficiency Induces Hepatic Steatosis Through Inhibitionmentioning

confidence: 99%

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Glutaredoxin-1 Deficiency Causes Fatty Liver and Dyslipidemia by Inhibiting Sirtuin-1

Шао

Han

Hou

et al. 2017

Antioxidants & Redox Signaling

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Rebamipide potentially mitigates methotrexate‐induced nephrotoxicity via inhibition of oxidative stress and inflammation: A molecular and histochemical study

Elmansy

Seleem

Mahmoud

et al. 2020

The Anatomical Record

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Methotrexate (MTX) is a widely used chemotherapeutic agent; nevertheless, the nephrotoxicity associated with its use has limited its clinical use. Rebamipide (REB) is a gastro‐protective agent with diverse promising biological activities. Here, we investigated the renoprotective effects of REB against MTX‐induced nephrotoxicity in rats. Male Wistar rats were allocated into four groups: the normal control group, the REB group (100 mg kg−1 day−1, PO, for 12 days), the MTX group (which received a single injection of 20 mg/kg, ip), and the REB + MTX group (which received 100 mg kg−1 day−1 REB for 7 days before and 5 days after being injected with 20 mg/kg MTX). Interestingly, MTX triggered kidney injury, characterized by renal dysfunction along with histopathological alterations. Moreover, increased reactive oxygen species level and inflammatory response were detected in the kidney of MTX‐treated rats. However, REB prevented MTX‐induced oxidative kidney injury and boosted an antioxidant balance. Mechanistically, REB markedly activated the NRF‐2 protein and upregulated the expression of both SIRT‐1 and FOXO‐3 genes. Additionally, REB administration strongly inhibited the inflammatory response by downregulating both NF‐κB‐p65 and TLR‐4. Finally, the coadministration of REB and MTX activated the mTOR/PI3K/AKT signaling pathway. Simultaneously, REB treatment attenuated the reduction in glomerular size, the widening of the capsular spaces, and the tubular cell damage due to MTX administration. Taken together, these results indicate the potential of REB as adjuvant therapy to prevent nephrotoxicity in patients receiving MTX treatment.

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Molecular mechanisms underlying methotrexate-induced intestinal injury and protective strategies

Ali,

Hassanein,

Mohamed

2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Methotrexate (MTX) is a folic acid reductase inhibitor that manages various malignancies as well as immune-mediated inflammatory chronic diseases. Despite being frequently prescribed, MTX’s severe multiple toxicities can occasionally limit its therapeutic potential. Intestinal toxicity is a severe adverse effect associated with the administration of MTX, and patients are significantly burdened by MTX-provoked intestinal mucositis. However, the mechanism of such intestinal toxicity is not entirely understood, mechanistic studies demonstrated oxidative stress and inflammatory reactions as key factors that lead to the development of MTX-induced intestinal injury. Besides, MTX causes intestinal cells to express pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which activate nuclear factor-kappa B (NF-κB). This is followed by the activation of the Janus kinase/signal transducer and activator of the transcription3 (JAK/STAT3) signaling pathway. Moreover, because of its dual anti-inflammatory and antioxidative properties, nuclear factor erythroid-2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) has been considered a critical signaling pathway that counteracts oxidative stress in MTX-induced intestinal injury. Several agents have potential protective effects in counteracting MTX-provoked intestinal injury such as omega-3 polyunsaturated fatty acids, taurine, umbelliferone, vinpocetine, perindopril, rutin, hesperidin, lycopene, quercetin, apocynin, lactobacillus, berberine, zinc, and nifuroxazide. This review aims to summarize the potential redox molecular mechanisms of MTX-induced intestinal injury and how they can be alleviated. In conclusion, studying these molecular pathways might open the way for early alleviation of the intestinal damage and the development of various agent plans to attenuate MTX-mediated intestinal injury. Graphical Abstract

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A Redox-resistant Sirtuin-1 Mutant Protects against Hepatic Metabolic and Oxidant Stress

Cited by 62 publications

References 71 publications

Glutaredoxin-1 Deficiency Causes Fatty Liver and Dyslipidemia by Inhibiting Sirtuin-1

Glutaredoxin-1 Deficiency Causes Fatty Liver and Dyslipidemia by Inhibiting Sirtuin-1

Rebamipide potentially mitigates methotrexate‐induced nephrotoxicity via inhibition of oxidative stress and inflammation: A molecular and histochemical study

Molecular mechanisms underlying methotrexate-induced intestinal injury and protective strategies

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