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sirtuins在酒精性肝病及脂多糖诱导的肝损伤中的作用及机制

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Sirtuins在酒精性肝病及脂多糖诱导的肝损伤中的作用及机制

作者：阮昕上海交通大学

学位级别：硕士

酒精性肝病(alcoholic liver diseases,ALD)包括一系列临床疾病和肝组织病理的变化,包括酒精性脂肪肝(alcoholic fatty liver,AFL)、酒精性肝炎(alcoholic hepatitis,AH)、酒精性肝纤维化(alcoholic hepatic fibrosis,AHF)、酒精性肝硬化(alcoholic cirrhosis,AC)甚至原发性肝细胞肝癌(hepatocellular carcinoma,HCC)。随着酒精消费在全世界范围内逐年增加,ALD的患病率和致死率也在逐渐增加。ALD的发病机制与乙醇及其代谢产物、脂多糖(lipopolysaccharide,LPS)、炎症免疫、衰老、内质网应激(ER Stress)等因素有关。但具体机制尚不明确,针对ALD的治疗尚缺乏有效的药物。sirtuin蛋白家族是一类NAD依赖的去乙酰基转移酶,一共有7个成员,SIRT1-SIRT7。本研究分别构建了新型酒精性肝病模型和LPS诱导的急性肝损伤小鼠模型,利用H&E染色比较各组小鼠肝脏病理学改变,同时观察血清学生化指标的变化;利用TUNEL染色和F4/80染色明确小鼠肝脏内细胞凋亡和炎症浸润程度;利用转录组测序分析肝损伤的相关分子,进一步通过体外实验分别研究SIRT2和SIRT7在不同因素导致的肝损伤中的作用及分子机制。实验结果发现:SIRT2通过增加C/EBPβ和急性期蛋白减轻ALD;在LPS诱导的急性肝损伤模型中,SIRT2在年轻小鼠中不发挥作用,但加重LPS诱导的衰老小鼠的肝损伤;同时,SIRT7能够通过抑制ER Stress中的GRP78减轻LPS诱导的肝损伤。以上结果提示:sirtuins在不同因素导致的肝损伤中的作用不同,因此,sirtuins可以作为针对病因及年龄等因素进行肝损伤精准治疗的潜在靶点。

关键词： sirtuin SIRT2 SIRT7 酒精性肝病衰老脂多糖内质网应激

A dual-function chemical probe for detecting erasers of lysine lipoylation

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Frontiers of Chemical Science and Engineering 2022年第1期16卷 121-127页

作者： Yusheng Xie Jie Zhang Liu Yang Qingxin Chen Quan Hao Liang Zhang Hongyan Sun Department of Chemistry City University of Hong KongHong KongChina Key Laboratory of Biochip Technology Biotech and Health CentreCity University of Hong Kong Shenzhen Research InstituteShenzhen 518057China School of Biomedical Sciences University of Hong KongHong KongChina Department of Biomedical Science College of Veterinary Medicine and Life SciencesCity University of Hong KongHong KongChina

Lysine lipoylation plays vital roles in cell metabolism and redox *** example,removal of lipoylation will decrease pyruvate dehydrogenase activity and affect the citric acid *** the important functions of lysine lipoylation,the mechanisms for the addition and removal of this modification remain largely *** few useful chemical tools are available to study the interactions of lysine lipoylation with its regulatory delipoylation *** example,immunoaffinity purification-mass spectrometry is one of such tools,which highly relies on antibody efficiency and purification ***-step activity based fluorogenic probes developed by our groups and others is also an efficient method to study the deacylation *** labeling probe using photo-cross-linker is a powerful platform to study the transient and dynamic interactions of peptide ligands with the interacting ***,we have designed and synthesized a dual-function probe KTLlip for studying enzymatic delipoylation(eraser)activity and interaction of lysine lipoylation with the eraser at the same *** show that KTLlip can be used as a useful tool to detect delipoylation as demonstrated by its ability to fluorescently label the eraser activity of recombinant *** envision that the probe will help delineate the roles of delipoylation enzyme in biology.

关键词： dual-function fluorescent probe labeling photo-cross-linker lipoylation modification eraser sirtuin

SIRT1-dependent modulation of methylation and acetylation of histone H3 on lysine 9(H3K9)in the zygotic pronuclei improves porcine embryo development

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Journal of Animal Science and Biotechnology 2018年第2期9卷 339-350页

作者： Katerina Adamkova Young-Joo Yi Jaroslav Petr Tereza Zalmanova Kristyna Hoskova Pavla Jelinkova Jiri Moravec Milena Kralickova Miriam Sutovsky Peter Sutovsky Jan Nevoral Department of Veterinary Sciences Faculty of AgricultureFood and Natural ResourcesCzech University of Life Sciences Prague6-SuchdolPragueCzech Republic Division of Biotechnology SafetyEnvironment and Life Science InstituteCollege of Environmental and Bioresource SciencesChonbuk National UniversityIksan 54596South Korea Institute of Animal Science 10-UhrinevesPragueCzech Republic Proteomic Laboratory Biomedical Center of Faculty of Medicine in PilsenCharles UniversityPilsenCzech Republic Laboratory of Reproductive Medicine of Biomedical Center Charles UniversityPilsenCzech Republic Department of Histology and Embryology Faculty of Medicine in PilsenCharles UniversityPilsenCzech Republic Division of Animal Science University of MissouriColumbiaMOUSA Departments of Obstetrics Gynecology and Women’s HealthUniversity of MissouriColumbiaMOUSA

Background: The histone code is an established epigenetic regulator of early embryonic development in *** lysine residue K9 of histone H3(H3 K9) is a prime target of SIRT1, a member of NAD+-dependent histone deacetylase family of enzymes targeting both histone and non-histone substrates. At present, little is known about SIRT1-modulation of H3 K9 in zygotic pronuclei and its association with the success of preimplantation embryo development. Therefore, we evaluated the effect of SIRT1 activity on H3 K9 methylation and acetylation in porcine zygotes and the significance of H3 K9 modifications for early embryonic ***: Our results show that SIRT1 activators resveratrol and BML-278 increased H3 K9 methylation and suppressed H3 K9 acetylation in both the paternal and maternal pronucleus. Inversely, SIRT1 inhibitors nicotinamide and sirtinol suppressed methylation and increased acetylation of pronuclear H3 K9. Evaluation of early embryonic development confirmed positive effect of selective SIRT1 activation on blastocyst formation rate(5.2 ± 2.9% versus 32.9 ± 8.1% in vehicle control and BML-278 group, respectively; P ≤ 0.05). Stimulation of SIRT1 activity coincided with fluorometric signal intensity of ooplasmic ubiquitin ligase MDM2, a known substrate of SIRT1 and known limiting factor of epigenome ***: We conclude that SIRT1 modulates zygotic histone code, obviously through direct deacetylation and via non-histone targets resulting in increased H3 K9 me3. These changes in zygotes lead to more successful pre-implantation embryonic development and, indeed, the specific SIRT1 activation due to BML-278 is beneficial for in vitro embryo production and blastocyst achievement.

关键词： Embryonic development Epigenetics H3K9 methylation SIRT1 sirtuin

Histone Deacetylase AtSRT1 Links Metabolic Flux and Stress Response in Arabidopsis

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Molecular Plant 2017年第12期10卷 1510-1522页

作者： Xiaoyun Liu Wei Wei Wenjun Zhu Lufang Su Zeyang Xiong Man Zhou Yu Zheng and Dao-Xiu Zhou Institute for Interdisciplinary Research Jianghan University Wuhan 430056 China Institute Plant Science Paris-Saclay (IPS2) CNRS INRA Universite Paris-sud 11 Univeraite Paris-Saclay B630 91405 Orsay France College of Biology and Pharmaceutical Engineering Wuhan Polytechnic University Wuhan 430023 China These authors contributed equally to this article.

How plant metabolic flux alters gene expression to optimize plant growth and response to stress remains largely unclear. Here, we report that Arabidopsis thaliana NAD＊-dependent histone deacetylase AtSRT1 negatively regulates plant tolerance to stress and glycolysis but stimulates mitochondrial respiration. We found that AtSRT1 interacts with Arabidopsis cMyc-Binding Protein 1 （AtMBP-1）, a transcriptional repressor produced by alternative translation of the cytosolic glycolytic enolase gene LOS2/EN02. We demonstrated that AtSRT1 could associate with the chromatin of AtMBP-I targets LOS2/EN02 and STZ/ZATIO, both of which encode key stress regulators, and reduce the H3K9ac levels at these genes to repress their transcription. Overexpression of both AtSRT1 and AtMBP-1 had synergistic effects on the expression of glycolytic genes, glycolytic enzymatic activities, and mitochondrial respiration. Furthermore, we found that AtMBP-1 is lysine-acetylated and vulnerable to proteasomal protein degradation, while AtSRT1 could remove its lysine acetylation and significantly enhance its stability in vivo. Taken together, these results indicate that AtSRT1 regulates primary metabolism and stress response by both epigenetic regulation and modulation of AtMBP-1 transcriptional activity in Arabidopsis.

关键词： chromartin histone modification HDAC sirtuin lysine acetylation metabolism

Network-centric medicine for peripheral nerve injury:treating the whole to boost endogenous mechanisms of neuroprotection and regeneration

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Neural Regeneration Research 2019年第7期14卷 1122-1128页

作者： David Romeo-Guitart Caty Casas Institut de Neurociències(INc) and Department of Cell Biology Physiology and ImmunologyUniversitat Autònoma de Barcelona (UAB) & Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas(CIBERNED)

Peripheral nerve injuries caused by accidents may lead to paralysis,sensory disturbances,anaesthesia,and lack of autonomic *** recovery after disconnection of the motoneuronal soma from target tissue with proximal rupture of axons is determined by several factors:motoneuronal soma viability,proper axonal sprouting across inhibitory zones and elongation toward specific muscle,effective synapse contact rebuilding,and prevention of muscle ***,such as adjuvant drugs with pleiotropic effects,that promote functional recovery after peripheral nerve injury are *** this aim,we designed a drug discovery workflow based on a network-centric molecular vision using unbiased proteomic data and neural artificial computational *** focus is on boosting intrinsic capabilities of neurons for neuroprotection;this is in contrast to the common approach based on suppression of a pathobiological pathway known to be associated with disease *** our workflow,we discovered neuroheal,a combination of two repurposed drugs that promotes motoneuronal soma neuroprotection,is anti-inflammatory,enhances axonal regeneration after axotomy,and reduces muscle *** drug discovery workflow has thus yielded a therapy that is close to its clinical application.

关键词： motoneuron neurodegeneration axonal regeneration muscle atrophy systems biology neuroheal PI3K/AKT sirtuin 1 motor function recovery

The effects of nicotinamide adenine dinucleotide in cardiovascular diseases: Molecular mechanisms, roles and therapeutic potential

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Genes & Diseases 2022年第4期9卷 959-972页

作者： Xiaokai Zhang Yang Zhang Aijun Sun Junbo Ge Department of Cardiology Zhongshan HospitalFudan UniversityShanghai Institute of Cardiovascular DiseasesShanghai 200032PR China Institute of Biomedical Sciences Fudan UniversityShanghai 200032PR China

Recently, cardiovascular diseases (CVDs) were identified as the leading cause of mortality, imposing a heavy burden on health care systems and the social economy. Nicotinamide adenine dinucleotide (NAD+), as a pivotal co-substrate for a range of different enzymes, is involved in many signal transduction pathways activated in CVDs. Emerging evidence has shown that NAD+ can exert remediating effects on CVDs by regulating metabolism, maintaining redox homeostasis and modulating the immune response. In fact, NAD+ might delay ageing through sirtuin and non-sirtuin pathways and thus contribute to interventions for age-related diseases such as CVDs. Considering that robust clinical studies of NAD+ are ongoing, we discuss current challenges and the future translational potential of NAD+ based on existing studies and our understanding. Despite some remaining gaps in its clinical application, NAD+ has been shown to have broad prospects and pan-effects, making it a suitable prophylactic drug for CVDs.

关键词： Ageing Cardiovascular disease Metabolism Nicotinamide adenine dinucleotide sirtuin

The effect of caloric restriction on genetical pathways

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Food Science and Human Wellness 2023年第5期12卷 1450-1457页

作者： Mustafa Fevzi Karagöz A.Gülçin Sağdıçoğlu Celep Faculty of Health Sciences Department of Nutrition and DieteticsGazi UniversityÇankaya 06490Turkey

Energy restriction is defined as reducing nutrient intake without dragging the organism into malnutrition. Energy restriction is preferred because it is a non-genetic intervention that increases life expectancy. Nicotinamide adenine dinucleotide(NAD~+)and adenosine monophosphate(AMP)levels, which are the indicators of intracellular energy deficiency, increase with energy restriction. The increase in NAD~+ level stimulates sirtuin(SIRT)enzymes, and the increase in AMP level stimulates AMP-activated protein kinase(AMPK). Various mechanisms are regulated by stimulating these enzymes. By Forkhead box O(FoxO)transcription factors, the ability of resistance to oxidative stress increases, and antioxidant genes, DNA repair, and autophagy genes are stimulated. Apoptosis is induced by stimulation of the p53 protein, and tumor growth is suppressed by the disruption of aging cells. The suppression of phosphoinositide 3-kinase(PI3K)-/-Akt, and therefore mTOR signal stimulates autophagy and mitophagia, and cleanses damaged cells and organelles. Mitochondrial biogenesis is stimulated, antioxidant capacity increases, and inflammatory response decreases. Adipose tissue and lipid metabolism are regulated by the regulation of fatty acid synthesis and oxidation. As a consequence, the effects of caloric restriction on cellular metabolism are regulated through the genetic pathways.

关键词： Caloric restriction Energy restriction sirtuin AMPK Mitochondrial biogenesis

Melatonin modifies SOX2^+ cell proliferation in dentate gyrus and modulates SIRT1 and MECP2 in long-term sleep deprivation

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Neural Regeneration Research 2019年第10期14卷 1787-1795页

作者： Alan Hinojosa-Godínez Luis F. Jave-Suarez Mario Flores-Soto Alma Y. Gálvez-Contreras Sonia Luquín Edith Oregon-Romero Oscar González-Pérez Rocio E. González-Castaneda Laboratorio de Microscopía de Alta Resolución Departamento de NeurocienciasCentro Universitario de Ciencias de la SaludUniversidad de GuadalajaraGuadalajaraMéxico Laboratorio de Neurociencias Facultad de PsicologíaUniversidad de ColimaColimaMéxico División de Inmunología Centro de Investigación Biomédica de OccidenteInstituto Mexicano del Seguro SocialGuadalajaraMéxico División de Neurociencias Centro de Investigación Biomédica de OccidenteInstituto Mexicano del Seguro SocialGuadalajaraMéxico Instituto de Investigación en Ciencias Biomédicas (IICB) Departamento de Biología Molecular y GenómicaCentro Universitario de Ciencias de la SaludUniversidad de GuadalajaraGuadalajaraMéxico Unidad de Atención en Neurociencias Departamento de Neurociencias. Centro Universitario de Ciencias de la SaludUniversidad de GuadalajaraGuadalajaraMéxico

Melatonin is a pleiotropic molecule that,after a short-term sleep deprivation,promotes the proliferation of neural stem cells in the adult ***,this effect has not been observed in long-term sleep *** precise mechanism exerted by melatonin on the modulation of neural stem cells is not entirely elucidated,but evidence indicates that epigenetic regulators may be involved in this *** this study,we investigated the effect of melatonin treatment during a 96-hour sleep deprivation and analyzed the expression of epigenetic modulators predicted by computational text mining and keyword *** results showed that the administration of melatonin under sleep-deprived conditions increased the MECP2 expression and reduced the SIRT1 expression in the dentate *** observed that let-7 b,mir-132,and mir-124 were highly expressed in the dentate gyrus after melatonin administration,but they were not modified by sleep *** addition,we found more Sox2^+/5-bromo-2’-deoxyuridine(BrdU)^+cells in the subgranular zone of the sleep-deprived group treated with melatonin than in the untreated *** findings may support the notion that melatonin modifies the expression of epigenetic mediators that,in turn,regulate the proliferation of neural progenitor cells in the adult dentate gyrus under long-term sleep-deprived *** procedures performed in this study were approved by the Animal Ethics Committee of the University of Guadalajara,Mexico(approval ***-16610)on January 2,2016.

关键词： sleep-deprivation melatonin microRNA neurogenesis sirtuin 1 SIRT1 methyl-CpG-binding protein 2 MECP2 epigenetic text-mining mir-9 let-7b

Epigenetic and non-epigenetic mode of SIRT1 action during oocyte meiosis progression

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Journal of Animal Science and Biotechnology 2019年第4期10卷 895-906页

作者： Jan Nevoral Lukas Landsmann Miriam Stiavnicka Petr Hosek Jiri Moravec Sarka Prokesova Hedvika Rimnacova Eliska Koutna Pavel Klein Kristyna Hoskova Tereza Zalmanova Tereza Fenclova Jaroslav Petr Milena Kralickova Biomedical Center Faculty of Medicine in PilsenCharles Universityalej Svobody 1655/7632300 PilsenCzech Republic Department of Histology and Embryology Faculty of Medicine in PilsenCharles UniversityKarlovarska 4830166 PilsenCzech Republic Faculty of Science Charles UniversityAlbertov 2038/612800 PragueCzech Republic Faculty of Agriculture Food and Natural ResourcesCzech University of Life Sciences in PragueKamycka 12916500 Praha-SuchdolCzech Republic Institute of Animal Science Pratelstvi 815/10710400Prague 10-UhrinevesCzech Republic

Background: SIRT1 histone deacetylase acts on many epigenetic and non-epigenetic targets. It is thought that SIRT1 is involved in oocyte maturation;therefore, the importance of the ooplasmic SIRT1 pool for the further fate of mature oocytes has been strongly suggested. We hypothesised that SIRT1 plays the role of a signalling molecule in mature oocytes through selected epigenetic and non-epigenetic ***: We observed SIRT1 re-localisation in mature oocytes and its association with spindle *** mature oocytes, SIRT1 distribution shows a spindle-like pattern, and spindle-specific SIRT1 action decreasesα-tubulin acetylation. Based on the observation of the histone code in immature and mature oocytes, we suggest that SIRT1 is mostly predestined for an epigenetic mode of action in the germinal vesicles(GVs) of immature oocytes. Accordingly, BML-278-driven trimethylation of lysine K9 in histone H3 in mature oocytes is considered to be a result of GV epigenetic ***: Taken together, our observations point out the dual spatiotemporal SIRT1 action in oocytes,which can be readily switched from the epigenetic to non-epigenetic mode of action depending on the progress of meiosis.

关键词： Epigenetics Histone code In vitro maturation Oocyte SIRT1 sirtuin 1