β-羟丁酸介导的表观遗传修饰及其调节炎症反应分子机制研究进展

doi:10.11843/j.issn.0366-6964.2023.10.009

畜牧兽医学报 ›› 2023, Vol. 54 ›› Issue (10): 4095-4104.doi: 10.11843/j.issn.0366-6964.2023.10.009

β-羟丁酸介导的表观遗传修饰及其调节炎症反应分子机制研究进展

戴伶俐^1,3, 刘在霞¹, 郭丽丽², 杨彦达¹, 常晨城¹, 王宇⁴, 石彩霞¹, 王玉珍², 张文广^1,2*

1. 内蒙古农业大学动物科学学院, 呼和浩特 010018;
2. 内蒙古农业大学生命科学学院, 呼和浩特 010018;
3. 内蒙古自治区农牧业科学院, 呼和浩特 010031;
4. 内蒙古农业大学兽医学院, 呼和浩特 010018

收稿日期:2022-12-19 出版日期:2023-10-23 发布日期:2023-10-26
通讯作者: 张文广,主要从事牛羊基因组育种、生物信息学、人工智能及农业信息化等方面的研究,E-mail:wenguangzhang@imau.edu.cn
作者简介:戴伶俐(1983-),女,黑龙江大庆人,博士生,主要从事功能基因组与天然免疫研究,E-mail:lingli20022006@sina.com
基金资助:
内蒙古自治区直属高校基本科研业务项目（RZ2200001019）；内蒙古自治区自然科学基金重大项目（2021ZD05）；内蒙古自治区科技计划（2021GG0025；2021GG0008）；内蒙古农业大学动物科学学院标志性成果专项资金项目（BZCG201903）

β-Hydroxybutyrate Mediated Epigenetic Modification and Its Molecular Mechanism of Regulating Inflammation

DAI Lingli^1,3, LIU Zaixia¹, GUO Lili², YANG Yanda¹, CHANG Chencheng¹, WANG Yu⁴, SHI Caixia¹, WANG Yuzhen², ZHANG Wenguang^1,2*

1. College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010018, China;
2. College of Life Science, Inner Mongolia Agricultural University, Hohhot 010018, China;
3. Inner Mongolia Academy of Agriculture and Animal Husbandry Sciences, Hohhot 010031, China;
4. College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot 010018, China

Received:2022-12-19 Online:2023-10-23 Published:2023-10-26

摘要/Abstract

摘要： 围产期奶牛经历不同程度的能量负平衡状态，严重的能量负平衡导致奶牛酮病，血液酮体浓度异常升高，降低奶牛的生产性能，并且常发生炎症性疾病。β-羟丁酸（β-hydroxybutyrate，BHBA）是主要的酮体分子，BHBA不仅可以作为能量物质供能，还能够介导表观遗传修饰调控基因转录表达，也能够作为信号分子与相应的受体结合，调控炎症反应。BHBA将外界环境变化与细胞功能改变联系起来，影响疾病进程。本文从BHBA信号传导角度进行综述，重点阐述BHBA影响表观遗传修饰改变基因转录调控，探讨了对炎症反应调节的分子机制，以期为代谢与炎症的研究提供新思路。

关键词: β-羟丁酸, 表观遗传修饰, 炎症, 代谢

Abstract: Dairy cows experience varying degrees of negative energy balance during the perinatal period. Severe negative energy balance leads to ketosis, abnormally elevated blood ketone body concentration, reduced performance, and often inflammatory diseases in dairy cows. β-hydroxybutyrate (BHBA) is a major ketone molecule. BHBA not only acts as an energy source, but also mediates epigenetic modifications that regulate gene transcription and expression, and can act as a signaling molecule that binds to the corresponding receptor to regulate the inflammatory response. BHBA links changes in the external environment to changes in cell function and affects disease processes. This review of BHBA signal transduction focuses on the effect of BHBA on epigenetic modification to alter gene transcription regulation, and explores the molecular mechanisms of BHBA in the regulation of inflammatory response, with the aim of providing new ideas for the study of metabolism and inflammation.

Key words: β-hydroxybutyrate, epigenetic modification, inflammation, metabolism

中图分类号:

S852.2

戴伶俐, 刘在霞, 郭丽丽, 杨彦达, 常晨城, 王宇, 石彩霞, 王玉珍, 张文广. β-羟丁酸介导的表观遗传修饰及其调节炎症反应分子机制研究进展[J]. 畜牧兽医学报, 2023, 54(10): 4095-4104.

DAI Lingli, LIU Zaixia, GUO Lili, YANG Yanda, CHANG Chencheng, WANG Yu, SHI Caixia, WANG Yuzhen, ZHANG Wenguang. β-Hydroxybutyrate Mediated Epigenetic Modification and Its Molecular Mechanism of Regulating Inflammation[J]. Acta Veterinaria et Zootechnica Sinica, 2023, 54(10): 4095-4104.

参考文献 56

[1]	DUFFIELD T. Subclinical ketosis in lactating dairy cattle[J]. Vet Clin North Am Food Anim Pract, 2000, 16(2):231-253.
[2]	GORDON J L, LEBLANC S J, DUFFIELD T F. Ketosis treatment in lactating dairy cattle[J]. Vet Clin North Am Food Anim Pract, 2013, 29(2):433-445.
[3]	靳军阳, 闫磊, 薛永康, 等. 围产期奶牛的能量负平衡及能量代谢障碍病防治[J]. 湖北畜牧兽医, 2018, 39(12):22-27.JIN J Y, YAN L, XUE Y K, et al. Negative energy balance and prevention of energy metabolism disorders in periparturient dairy cows[J]. Hubei Journal of Animal and Veterinary Sciences, 2018, 39(12):22-27. (in Chinese)
[4]	吴怡, 敖日格乐, 王纯洁, 等. 反刍动物围产期能量负平衡的调控研究进展[J]. 饲料研究, 2022, 45(2):136-140.WU Y, AO R G, WANG C J, et al. Research progress on regulation of negative energy balance in ruminants during perinatal period[J]. Feed Research, 2022, 45(2):136-140. (in Chinese)
[5]	CAHILL G F. Fuel metabolism in starvation[J]. Annu Rev Nutr, 2006, 26:1-22.
[6]	PUCHALSKA P, CRAWFORD P A. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics[J]. Cell Metab, 2017, 25(2):262-284.
[7]	OVERTON T R, MCART J A A, NYDAM D V. A 100-year review:metabolic health indicators and management of dairy cattle[J]. J Dairy Sci, 2017, 100(12):10398-10417.
[8]	NEWMAN J C, VERDIN E. Ketone bodies as signaling metabolites[J]. Trends Endocrinol Metab, 2014, 25(1):42-52.
[9]	RAHMAN M, MUHAMMAD S, KHAN M A, et al. The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages[J]. Nat Commun, 2014, 5:3944.
[10]	YOUM Y H, NGUYEN K Y, GRANT R W, et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease[J]. Nat Med, 2015, 21(3):263-269.
[11]	XIE Z Y, ZHANG D, CHUNG D, et al. Metabolic regulation of gene expression by histone lysine β-hydroxybutyrylation[J]. Mol Cell, 2016, 62(2):194-206.
[12]	RUI L Y. Energy metabolism in the liver[J]. Compr Physiol, 2014, 4(1):177-197.
[13]	ZHAO S, ZHANG X R, LI H T. Beyond histone acetylation-writing and erasing histone acylations[J]. Curr Opin Struct Biol, 2018, 53:169-177.
[14]	MURPHY P, LIKHODII S, NYLEN K, et al. The antidepressant properties of the ketogenic diet[J]. Biol Psychiatry, 2004, 56(12):981-983.
[15]	CHEN L, MIAO Z G, XU X S. β-Hydroxybutyrate alleviates depressive behaviors in mice possibly by increasing the histone3-lysine9-β-hydroxybutyrylation[J]. Biochem Biophys Res Commun, 2017, 490(2):117-122.
[16]	LUO W G, YU Y J, WANG H, et al. Up-regulation of MMP-2 by histone H3K9 β-hydroxybutyrylation to antagonize glomerulosclerosis in diabetic rat[J]. Acta Diabetol, 2020, 57(12):1501-1529.
[17]	ZHANG H F, TANG K, MA J W, et al. Ketogenesis-generated β-hydroxybutyrate is an epigenetic regulator of CD8+ T-cell memory development[J]. Nat Cell Biol, 2020, 22(1):18-25.
[18]	SANGALLI J R, NOCITI R P, DEL COLLADO M, et al. Characterization of histone lysine β-hydroxybutyrylation in bovine tissues, cells, and cumulus-oocyte complexes[J]. Mol Reprod Dev, 2022, 89(9):375-398.
[19]	KELLY R D W, CHANDRU A, WATSON P J, et al. Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation in vivo[J]. Sci Rep, 2018, 8(1):14690.
[20]	SHIMAZU T, HIRSCHEY M D, NEWMAN J, et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor[J]. Science, 2013, 339(6116):211-214.
[21]	SABARI B R, ZHANG D, ALLIS C D, et al. Metabolic regulation of gene expression through histone acylations[J]. Nat Rev Mol Cell Biol, 2017, 18(2):90-101.
[22]	SANGALLI J R, SAMPAIO R V, DEL COLLADO M, et al. Metabolic gene expression and epigenetic effects of the ketone body β-hydroxybutyrate on H3K9ac in bovine cells, oocytes and embryos[J]. Sci Rep, 2018, 8(1):13766.
[23]	HU E L, DU H, SHANG S, et al. Beta-hydroxybutyrate enhances BDNF expression by increasing H3K4me3 and decreasing H2AK119ub in hippocampal neurons[J]. Front Neurosci, 2020, 14:591177.
[24]	HU E L, DU H, ZHU X L, et al. Beta-hydroxybutyrate promotes the expression of BDNF in hippocampal neurons under adequate glucose supply[J]. Neuroscience, 2018, 386:315-325.
[25]	XU H W, WU M Y, MA X M, et al. Function and mechanism of novel histone posttranslational modifications in health and disease[J]. Biomed Res Int, 2021, 2021:6635225.
[26]	NASSER S, VIALICHKA V, BIESIEKIERSKA M, et al. Effects of ketogenic diet and ketone bodies on the cardiovascular system:concentration matters[J]. World J Diabetes, 2020, 11(12):584-595.
[27]	MCGETTRICK A F, O'NEILL L A J. How metabolism generates signals during innate immunity and inflammation[J]. J Biol Chem, 2013, 288(32):22893-22898.
[28]	陈华青, 刘明耀. G蛋白偶联受体及其信号转导在免疫与炎症中的作用[J]. 现代免疫学, 2009, 29(6):441-446.CHEN H Q, LIU M Y. The role of G protein-coupled receptors and their signal transduction in immunity and inflammation[J]. Current Immunology, 2009, 29(6):441-446. (in Chinese)
[29]	NEWMAN J C, VERDIN E. β-Hydroxybutyrate:a signaling metabolite[J]. Annu Rev Nutr, 2017, 37:51-76.
[30]	GRAFF E C, FANG H, WANDERS D, et al. Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2[J]. Metabolism, 2016, 65(2):102-113.
[31]	FU S P, LI S N, WANG J F, et al. BHBA suppresses LPS-induced inflammation in BV-2 cells by inhibiting NF-κB activation[J]. Mediators Inflamm, 2014, 2014:983401.
[32]	GAMBHIR D, ANANTH S, VEERANAN-KARMEGAM R, et al. GPR109A as an anti-inflammatory receptor in retinal pigment epithelial cells and its relevance to diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2012, 53(4):2208-2217.
[33]	VANHOLDER T, PAPEN J, BEMERS R, et al. Risk factors for subclinical and clinical ketosis and association with production parameters in dairy cows in the Netherlands[J]. J Dairy Sci, 2015, 98(2):880-888.
[34]	SHEN T Y, LI X W, LOOR J J, et al. Hepatic nuclear factor kappa B signaling pathway and NLR family pyrin domain containing 3 inflammasome is over-activated in ketotic dairy cows[J]. J Dairy Sci, 2019, 102(11):10554-10563.
[35]	CARRETTA M D, BARRÍA Y, BORQUEZ K, et al. β-Hydroxybutyrate and hydroxycarboxylic acid receptor 2 agonists activate the AKT, ERK and AMPK pathways, which are involved in bovine neutrophil chemotaxis[J]. Sci Rep, 2020, 10(1):12491.
[36]	MIELENZ M. Invited review:nutrient-sensing receptors for free fatty acids and hydroxycarboxylic acids in farm animals[J]. Animal, 2017, 11(6):1008-1016.
[37]	WEN H T, MIAO E A, TING J P Y. Mechanisms of NOD-like receptor-associated inflammasome activation[J]. Immunity, 2013, 39(3):432-441.
[38]	GOLDBERG E L, ASHER J L, MOLONY R D, et al. β-hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares[J]. Cell Rep, 2017, 18(9):2077-2087.
[39]	KONG G G, LIU J H, LI R, et al. Ketone metabolite β-hydroxybutyrate ameliorates inflammation after spinal cord injury by inhibiting the NLRP3 inflammasome[J]. Neurochem Res, 2021, 46(2):213-229.
[40]	YAMANASHI T, IWATA M, KAMIYA N, et al. Beta-hydroxybutyrate, an endogenic NLRP3 inflammasome inhibitor, attenuates stress-induced behavioral and inflammatory responses[J]. Sci Rep, 2017, 7(1):7677.
[41]	LUGRIN J, ROSENBLATT-VELIN N, PARAPANOV R, et al. The role of oxidative stress during inflammatory processes[J]. Biol Chem, 2014, 395(2):203-230.
[42]	HACES M L, HERNÁNDEZ-FONSECA K, MEDINA-CAMPOS O N, et al. Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions[J]. Exp Neurol, 2008, 211(1):85-96.
[43]	DONG Z H, SUN X D, TANG Y, et al. β-hydroxybutyrate impairs monocyte function via the ROS-NLR family pyrin domain-containing three inflammasome (NLRP3) pathway in ketotic cows[J]. Front Vet Sci, 2022, 9:925900.
[44]	GAO X X, ZHANG X, JIANG L Q, et al. Forsythin inhibits β-hydroxybutyrate-induced oxidative stress in bovine macrophages by regulating p38/ERK, PI3K/Akt, and Nrf2/HO-1 signaling pathways[J]. Res Vet Sci, 2023, 154:59-65.
[45]	SHI X X, LI X W, LI D D, et al. β-Hydroxybutyrate activates the NF-κB signaling pathway to promote the expression of pro-inflammatory factors in calf hepatocytes[J]. Cell Physiol Biochem, 2014, 33(4):920-932.
[46]	LONGO R, PERI C, CRICRÌ D, et al. Ketogenic diet:a new light shining on old but gold biochemistry[J]. Nutrients, 2019, 11(10):2497.
[47]	庄一民, 刁其玉, 张乃锋. 幼龄反刍动物瘤胃上皮细胞β-羟基丁酸代谢与调控机制[J]. 畜牧兽医学报, 2020, 51(4):660-669.ZHUANG Y M, DIAO Q Y, ZHANG N F. Metabolism and regulation mechanism of beta-hydroxybutyric acid in ruminal epithelium cells of young ruminants[J]. Acta Veterinaria et Zootechnica Sinica, 2020, 51(4):660-669. (in Chinese)
[48]	NORWITZ N G, JARAMILLO J G, CLARKE K, et al. Ketotherapeutics for neurodegenerative diseases[J]. Int Rev Neurobiol, 2020, 155:141-168.
[49]	FU S P, WANG J F, XUE W J, et al. Anti-inflammatory effects of BHBA in both in vivo and in vitro Parkinson's disease models are mediated by GPR109A-dependent mechanisms[J]. J Neuroinflammation, 2015, 12:9.
[50]	SHIPPY D C, WILHELM C, VIHARKUMAR P A, et al. β-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer's disease pathology[J]. J Neuroinflammation, 2020, 17(1):280.
[51]	FRISE C J, MACKILLOP L, JOASH K, et al. Starvation ketoacidosis in pregnancy[J]. Eur J Obstet Gynecol Reprod Biol, 2013, 167(1):1-7.
[52]	WANKHADE P R, MANIMARAN A, KUMARESAN A, et al. Metabolic and immunological changes in transition dairy cows:a review[J]. Vet World, 2017, 10(11):1367-1377.
[53]	STEENEVELD W, AMUTA P, VAN SOEST F J S, et al. Estimating the combined costs of clinical and subclinical ketosis in dairy cows[J]. PLoS One, 2020, 15(4):e0230448.
[54]	ALBAAJ A, JATTIOT M, MANCIAUX L, et al. Hyperketolactia occurrence before or after artificial insemination is associated with a decreased pregnancy per artificial insemination in dairy cows[J]. J Dairy Sci, 2019, 102(9):8527-8536.
[55]	ALERI J W, HINE B C, PYMAN M F, et al.Periparturient immunosuppression and strategies to improve dairy cow health during the periparturient period[J]. Res Vet Sci, 2016, 108:8-17.
[56]	赵婉莉, 曹棋棋, 杨悦, 等. 胃肠道菌群与黏膜免疫在围产期奶牛健康中的作用[J]. 畜牧兽医学报, 2023, 54(7):2751-2760.ZHAO W L, CAO Q Q, YANG Y, et al. The interaction between gastrointestinal microbiota and mucosal immunity in health of perinatal dairy cows[J]. Acta Veterinaria et Zootechnica Sinica, 2023, 54(7):2751-2760. (in Chinese)

β-羟丁酸介导的表观遗传修饰及其调节炎症反应分子机制研究进展

β-Hydroxybutyrate Mediated Epigenetic Modification and Its Molecular Mechanism of Regulating Inflammation

RichHTML

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献 56

相关文章 15

编辑推荐

Metrics

本文评价

[1]	杨小峰, 秦小伟, 吕丽华. MNQ的一种衍生物对LPS体外诱导的牛卵巢卵泡颗粒细胞炎性损伤的保护作用[J]. 畜牧兽医学报, 2024, 55(5): 2032-2041.
[2]	刘思弟, 马贲, 郑言, 邱云桥, 姚泽龙, 曹中赞, 栾新红. 肠道菌群调控动物肠道黏膜免疫和炎症的研究进展[J]. 畜牧兽医学报, 2024, 55(4): 1423-1431.
[3]	李菲菲, 张晨淼, 童津津, 蒋林树. 线粒体自噬调节NLRP3炎症小体活性改善动物健康的作用机制[J]. 畜牧兽医学报, 2024, 55(4): 1446-1455.
[4]	王中波, 刘爽, 贺丽霞, 冯雪, 杨梦丽, 汪书哲, 刘源, 冯兰, 丁晓玲, 冀国尚, 杨润军, 张路培, 马云. 固原黄牛不同部位肌肉组织代谢组学分析[J]. 畜牧兽医学报, 2024, 55(4): 1565-1578.
[5]	徐俊杰, 张璐通, 王津洁, 陈晓晨, 何伟先, 蔡传江, 褚瑰燕, 杨公社. 基于多组学与网络药理学探究淫羊藿对后备母猪发情的作用[J]. 畜牧兽医学报, 2024, 55(4): 1615-1628.
[6]	戴帆, 刘占有, 张旭阳, 李武. 乌头酸脱羧酶1对BCG诱导巨噬细胞炎症反应的调控作用研究[J]. 畜牧兽医学报, 2024, 55(4): 1696-1706.
[7]	卢劲晔, 高亚兵, 韩心茹, 刘钰臻, 赵家玉. 乳房链球菌感染对乳腺上皮细胞中氨基酸代谢的影响[J]. 畜牧兽医学报, 2024, 55(4): 1766-1776.
[8]	沈文娟, 杨卓, 张馨蕊, 付予, 陶金忠. 奶牛生殖道微生物与繁殖及相关疾病的研究进展[J]. 畜牧兽医学报, 2024, 55(3): 924-932.
[9]	易鹏飞, 孙磊, 马亚楠, 马雪连, 李娜, 孙亚伟, 钟旗, 姚刚. 健康安格斯犊牛与IBRV感染犊牛鼻腔菌群变化比较[J]. 畜牧兽医学报, 2024, 55(3): 1147-1158.
[10]	陈富斌, 徐国伟, 王磊, 刘琴, 冯海鹏, 张康, 郭志廷, 韩松伟, 刘佳惠, 古雪艳, 张景艳, 李建喜, Huub F. J. Savelkoul. 黄芪多糖对HD11鸡巨噬细胞转录组和代谢组的影响[J]. 畜牧兽医学报, 2024, 55(3): 1290-1301.
[11]	高欣, 孙怡朋. A型流感病毒诱导细胞炎症反应的研究进展[J]. 畜牧兽医学报, 2024, 55(2): 481-490.
[12]	宋明强, 解竞静, 欧娟, 王钰明, 侯嘉, 谭高明, 田凯, 朱云, 萨仁娜, 赵峰. 盐酸不溶灰分测定方法影响肉鸡饲粮代谢能准确性的比较研究[J]. 畜牧兽医学报, 2024, 55(2): 619-628.
[13]	王栋, 柳可欣, 何炎峻, 邓守翔, 刘云, 马卫明. 饲粮中添加腐殖酸钠对鼠伤寒沙门菌感染肉鸡肝组织炎症和抗氧化能力的影响[J]. 畜牧兽医学报, 2024, 55(2): 629-639.
[14]	陈雪清, 李志强, 吴雨龙, 张崇昊, 张源淑. 临床腹泻猪空肠组织中肾素-血管紧张素系统(RAS)的表达变化及与肠道炎症的关系[J]. 畜牧兽医学报, 2024, 55(2): 751-758.
[15]	刘益丽, 唐娇, 闵奇, 杨露, 王泽宁, 胡莲, 赵迪, 江明锋. 基于转录组数据挖掘牦牛皱胃发育代谢的关键候选基因[J]. 畜牧兽医学报, 2024, 55(1): 153-168.