Dataset Information

SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer.

ABSTRACT: Peroxisomes account for ~35% of total H2O2 generation in mammalian tissues. Peroxisomal ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in fatty acid β-oxidation and a major producer of H2O2 ACOX1 dysfunction is linked to peroxisomal disorders and hepatocarcinogenesis. Here, we show that the deacetylase sirtuin 5 (SIRT5) is present in peroxisomes and that ACOX1 is a physiological substrate of SIRT5. Mechanistically, SIRT5-mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation in both cultured cells and mouse livers. Deletion of SIRT5 increases H2O2 production and oxidative DNA damage, which can be alleviated by ACOX1 knockdown. We show that SIRT5 downregulation is associated with increased succinylation and activity of ACOX1 and oxidative DNA damage response in hepatocellular carcinoma (HCC). Our study reveals a novel role of SIRT5 in inhibiting peroxisome-induced oxidative stress, in liver protection, and in suppressing HCC development.

SUBMITTER: Chen XF

PROVIDER: S-EPMC5934778 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer.

Chen Xiu-Fei XF Tian Meng-Xin MX Sun Ren-Qiang RQ Zhang Meng-Li ML Zhou Li-Sha LS Jin Lei L Chen Lei-Lei LL Zhou Wen-Jie WJ Duan Kun-Long KL Chen Yu-Jia YJ Gao Chao C Cheng Zhou-Li ZL Wang Fang F Zhang Jin-Ye JY Sun Yi-Ping YP Yu Hong-Xiu HX Zhao Yu-Zheng YZ Yang Yi Y Liu Wei-Ren WR Shi Ying-Hong YH Xiong Yue Y Guan Kun-Liang KL Ye Dan D

EMBO reports 20180228 5

Peroxisomes account for ~35% of total H2O2 generation in mammalian tissues. Peroxisomal ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in fatty acid β-oxidation and a major producer of H2O2 ACOX1 dysfunction is linked to peroxisomal disorders and hepatocarcinogenesis. Here, we show that the deacetylase sirtuin 5 (SIRT5) is present in peroxisomes and that ACOX1 is a physiological substrate of SIRT5. Mechanistically, SIRT5-mediated desu ...[more]

PMID: 29491006

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Project description:Natural products like gallic acid (GA), a phenolic compound, and glycyrrhetinic acid (GLA), a pentacyclic triterpene, have been shown to exhibit antioxidant, ant-inflammatory, and hepatoprotective properties. This study aims to investigate the protective effects of GA, GLA and their combination and to explore their underlying mechanisms against acute liver damage induced by azithromycin (AZM) in rats. Seven groups of male Wistar rats were used namely control, GA, GLA, AZM, AZM + GA, AZM + GLA, and AZM + GA + GLA groups. We treated the rats for 21 days, administering GA and GLA at 50 mg/kg one week prior to AZM (30 mg/kg). Serum levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase in rats AZM-induced and pre-treated with of GA, GLA, and combination therapy were much lower than those in the AZM group Elevated levels of glutathione, catalase, and superoxide dismutase in preventive rats demonstrated that GA, GLA, and their combinations notably reduced AZM-induced malondialdehyde levels, an oxidative stress marker, improving the antioxidant system in those groups. Furthermore, GA, GLA, and their combinations reduced pro-inflammatory cytokines, such as tumor necrosis factor-α and nuclear factor kappa beta (NF-kB), thus reversing hepatic inflammation. We also discovered that AZM down-regulated nuclear factor erythroid 2-related factor 2 (Nrf2), and that its normal levels were restored post treatments with GA, GLA, and their combination suggesting a Nrf2 signaling pathway-mediated prevention of AZM-induced liver damage. In conclusion, GA, GLA, and their combination protected rats against AZM-induced liver injury through their demonstrated ability to lower oxidative stress and inflammation by preventing downregulation of Nrf2 and upregulation of NF-kB. After determining their efficacy and safety in clinical settings in future studies, GA and GLA could potentially make useful therapeutic drugs to mitigate AZM-induced hepatotoxicity.

Project description:BackgroundEosinophilic meningitis, caused by fifth-stage larvae of the nematode (roundworm) Angiostrongylus cantonensis, is mainly attributed to the contribution of eosinophils to tissue inflammatory responses in helminthic infections. Eosinophils are associated with the killing of helminths via peroxidative oxidation and hydrogen peroxide generated by the dismutation of superoxide produced during respiratory bursts. In contrast, when residing in the host with high level of eosinophils, helminthic worms have evolved to attenuate eosinophil-mediated tissue inflammatory responses for their survival in the hosts. In a previous study we demonstrated that the expression of the A. cantonensis RPS 30 gene (Acan-rps-30) was significantly downregulated in A. cantonensis L5 roundworms residing in cerebrospinal fluid with a high level of eosinophils. Acan-RPS-30 is a protein homologous to the human Fau protein that plays a pro-apoptotic regulatory role and may function in protecting worms from oxidative stress.MethodsThe isolation and structural characterization of Acan-RPS-30 were performed using rapid amplification of cDNA ends (RACE), genome walking and bioinformatics. Quantitative real-time-PCR and microinjection were used to detect the expression patterns of Acan-rps-30. Feeding RNA interference (RNAi) was used to knockdown the apoptosis gene ced-3. Microinjection was performed to construct transgenic worms. An oxidative stress assay was used to determine the functions of Acan-RPS-30.ResultsOur results showed that Acan-RPS-30 consisted of 130 amino acids. It was grouped into clade V with C. elegans in the phylogenetic analysis. It was expressed ubiquitously in worms and was downregulated in both L5 larvae and adult A. cantonensis. Worms expressing pCe-rps30::Acan-rps-30::rfp, with the refractile "button-like" apoptotic corpses, were susceptible to oxidative stress. Apoptosis genes ced-3 and ced-4 were both upregulated in the transgenic worms. The phenotype susceptible to oxidative stress could be converted with a ced-3 defective mutation and RNAi. rps-30-/- mutant worms were resistant to oxidative stress, with ced-3 and ced-4 both downregulated. The oxidative stress-resistant phenotype could be rescued and inhibited by through the expression of pCe-rps30::Acan-rps-30::rfp in rps-3-/- mutant worms.ConclusionIn C. elegans worms, downregulated RPS-30 plays a defensive role against damage due to oxidative stress, facilitating worm survival by regulating downregulated ced-3. This observation may indicate the mechanism by which A. cantonensis L5 worms, with downregulated Acan-RPS-30, survive in the central nervous system of humans from the immune response of eosinophils.

Dataset Information

SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer.

Publications

SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer.

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