生物钟基因在非酒精性脂肪性肝病发生发展中的作用

艾燕; 杨小倩; 潘晓莉; 叶进

doi:10.3969/j.issn.1001-5256.2019.10.043

生物钟基因在非酒精性脂肪性肝病发生发展中的作用

DOI: 10.3969/j.issn.1001-5256.2019.10.043

华中科技大学同济医学院附属协和医院消化内科

基金项目:

国家自然科学基金资助项目(81770582,81500444)；

详细信息

中图分类号: R575.5
计量
- 文章访问数: 767
- HTML全文浏览量: 18
- PDF下载量: 289
- 被引次数: 0
出版历程
- 收稿日期: 2019-05-20
- 出版日期: 2019-10-20

Role of circadian clock genes in the development and progression of nonalcoholic fatty liver disease

Division of Gastroenterology,Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology

Research funding:

摘要

摘要: 生物钟是生物体为了适应昼夜交替引起的光照、温度等变化而在漫长的进化过程中形成的内在变化节律。人类生物钟在分子水平上由多个生物钟基因精确调控;在解剖水平上由中枢生物钟和外周生物钟分级调控。近年来研究发现,生物钟基因可通过对下游钟控基因的调控参与细胞内的脂质代谢,并且有研究证实生物钟基因紊乱可导致与非酒精性脂肪性肝病(NAFLD)发病密切相关的脂代谢异常、氧化应激、胰岛素抵抗、糖皮质激素及炎症因子分泌异常等,生物钟基因的紊乱可增加临床上脂肪肝的易感性,这可以作为生物钟基因和NAFLD相关性研究的桥梁。现阶段NAFLD的发病机制尚不明确,综述了近年来国内外对生物钟基因及NAFLD的研究,旨在为进一步明确NAFLD的发病机制提供理论基础。
- 非酒精性脂肪性肝病 /
- 生物钟 /
- 基因
Abstract: Circadian clock is an inherent biological rhythm of organism which forms in the long process of evolution to adapt to the changes in light and temperature due to day-night alternation. Circadian clock in humans is accurately regulated by various circadian clock genes at the molecular level and are hierarchically regulated by the central clock and the peripheral clock at the anatomical level. Recent studies have found that circadian clock genes can participate in intracellular lipid metabolism by regulating downstream clock-controlled genes,and the disorder of circadian clock genes can result in abnormal lipid metabolism,oxidative stress,insulin resistance,and abnormal secretion of glucocorticoids and inflammatory factors,which are closely associated with the pathogenesis of nonalcoholic fatty liver disease(NAFLD). The disorder of circadian clock genes can also increase the susceptibility to fatty liver disease and thus acts as a bridge that connects circadian clock genes and NAFLD. The pathogenesis of NAFLD remains unclear at present,and therefore,this article summarizes the recent studies on the association between circadian clock genes and NAFLD,so as to provide a theoretical basis for further clarifying the pathogenesis of NAFLD.
- non-alcoholic fatty liver disease /
- biological clocks /
- genes

HTML全文

参考文献(49)

[1] ESLAM M,GEORGE J. Genetic and epigenetic mechanisms of NASH[J]. Hepatol Int,2016,10(3):394-406.

[2] YANG YL,ZHENG LY,GU WM,et al. Effect of total glucosides of paeony regulate HMGB1,RAGE pathway on nonalcoholic fatty liver disease in rats[J]. Chin J Clin Pharmacol Ther,2017,22(6):611-616.(in Chinese)杨以琳,郑琳颖,古伟明,等.白芍总苷对非酒精性脂肪性肝病大鼠HMGB1、RAGE通路的调控作用[J].中国临床药理学与治疗学,2017,22(6):611-616.

[3] YOUNOSSI ZM,KOENIG AB,ABDELATIF D,et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes[J]. Hepatology,2016,64(1):73-84.

[4] MENG YL,ZHANG HY,SONG BG,et al. An investigation of the prevalence rate of fatty liver disease among people undergoing physical examination in Tangshan,China[J]. J Clin Hepatol,2017,33(12):2376-2380.(in Chinese)孟昱林,张海艳,宋宝国,等.唐山市体检人群脂肪肝患病率调查分析[J].临床肝胆病杂志,2017,33(12):2376-2380.

[5] DIBNER C,SCHIBLER U,ALBRECHT U. The mammalian circadian timing system:Organization and coordination of central and peripheral clocks[J]. Annu Rev Physiol,2010,72:517-549.

[6] MOHAWK JA,GREEN CB,TAKAHASHI JS. Central and peripheral circadian clocks in mammals[J]. Annu Rev Neurosci,2012,35:445-462.

[7] GLASER FT,STANEWSKY R. Synchronization of the drosophila circadian clock by temperature cycles[J]. Cold Spring Harb Symp Quant Biol,2007,72:233-242.

[8] DAMIOLA F,LE MINH N,PREITNER N,et al. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus[J].Genes Dev,2000,14(23):2950-2961.

[9] KING DP,ZHAO Y,SANGORAM AM,et al. Positional cloning of the mouse circadian clock gene[J]. Cell,1997,89(4):641-653.

[10] LANDOLT HP. CIRCADIAN RHYTHMS. Caffeine,the circadian clock,and sleep[J]. Science,2015,349(6254):1289.

[11] CHO H,ZHAO X,HATORI M,et al. Regulation of circadian behaviour and metabolism by REV-ERB-alpha and REVERB-beta[J]. Nature,2012,485(7396):123-127.

[12] BERSTEN DC,SULLIVAN AE,PEET DJ,et al. bHLH-PAS proteins in cancer[J]. Nat Rev Cancer,2013,13(12):827-841.

[13] MAZZOCCOLI G,PAZIENZA V,VINCIGUERRA M. Clock genes and clock-controlled genes in the regulation of metabolic rhythms[J]. Chronobiol Int,2012,29(3):227-251.

[14] WILLEBRORDS J,PEREIRA IV,MAES M,et al. Strategies,models and biomarkers in experimental non-alcoholic fatty liver disease research[J]. Prog Lipid Res,2015,59:106-125.

[15] FANG YL,CHEN H,WANG CL,et al. Pathogenesis of nonalcoholic fatty liver disease in children and adolescence:From“two hit theory”to“multiple hit model”[J]. World J Gastroenterol,2018,24(27):2974-2983.

[16] ONYEKWERE CA,OGBERA AO,SAMAILA AA,et al. Nonalcoholic fatty liver disease:Synopsis of current developments[J]. Niger J Clin Pract,2015,18(6):703-712.

[17] WEI GC,HE JY. Traditional Chinese medicine intervention to nonalcoholic fatty liver disease based on physique identi cation[J]. J Changchun Univ Chin Med,2018,34(3):518-521.(in Chinese)魏功昌,何瑾瑜.中医体质辨识治疗非酒精性脂肪性肝病[J].长春中医药大学学报,2018,34(3):518-521.

[18] REBRIN K,STEIL GM,MITTELMAN SD,et al. Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs[J]. J Clin Invest,1996,98(3):741-749.

[19] SHULMAN GI. Ectopic fat in insulin resistance,dyslipidemia,and cardiometabolic disease[J]. N Engl J Med,2014,371(23):2237-2238.

[20] SACHDEV MS,RIELY CA,MADAN AK. Nonalcoholic fatty liver disease of obesity[J]. Obes Surg,2006,16(11):1412-1419.

[21] CARDOSO AR,CABRAL-COSTA JV,KOWALTOWSKI AJ. Effects of a high fat diet on liver mitochondria:Increased ATP-sensitive K+channel activity and reactive oxygen species generation[J]. J Bioenerg Biomembr,2010,42(3):245-253.

[22] FELDSTEIN AE,WERNEBURG NW,CANBAY A,et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway[J]. Hepatology,2004,40(1):185-194.

[23] TOMITA K,TAMIYA G,ANDO S,et al. Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice[J]. Gut,2006,55(3):415-424.

[24] PAZ-FILHO G,MASTRONARDI C,FRANCO CB,et al. Leptin:Molecular mechanisms, systemic pro-inflammatory effects,and clinical implications[J]. Arq Bras Endocrinol Metabol,2012,56(9):597-607.

[25] KAPIL S,DUSEJA A,SHARMA BK,et al. Small intestinal bacterial overgrowth andtoll-like receptor signaling in patients with non-alcoholic fatty liver disease[J]. J Gastroenterol Hepatol,2016,31(1):213-221.

[26] LANASPA MA,SANCHEZ-LOZADA LG,CHOI YJ,et al.Uric acid induces heaptic steatosis by generation of mitochondrial oxidative stress:Potential role in fructose-dependent and-independent fatty liver[J]. J Biol Chem,2012,287(48):40732-40744.

[27] GIUDICE EM,GRANDONE A,CIRILLO G,et al. The association of PNPLA3 variants with liver enzymes in childhood obesity is driven by the interaction with abdominal fat[J]. PLo S One,2011,6(11):e27933.

[28] ZANI F,BREASSON L,BECATTINI B,et al. PER2 promotes glucose storage to liver glycogen during feeding and acute fasting by inducing Gys2 PTG and G L expression[J]. Mol Metab,2013,2(3):292-305.

[29] GRIMALDI B,BELLET MM,KATADA S,et al. PER2 controls lipid metabolism by direct regulation of PPARgamma[J]. Cell Metab,2010,12(5):509-520.

[30] ZHOU D,WANG Y,CHEN L,et al. Evolving roles of circadian rhythms in liver homeostasis and pathology[J]. Oncotarget,2016,7(8):8625-8639.

[31] MARION-LETELLIER R,SAVOYE G,GHOSH S. Fatty acids,eicosanoids and PPAR gamma[J]. Eur J Pharmacol,2016,785:44-49.

[32] YANG G,JIA Z,AOYAGI T,et al. Systemic PPARgamma deletion impairs circadian rhythms of behavior and metabolism[J]. PLo S One,2012,7(8):e38117.

[33] LI S,LIN JD. Molecular control of circadian metabolic rhythms[J]. J Appl Physiol(1985),2009,107(6):1959-1964.

[34] FU J,GAETANI S,OVEISI F,et al. Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha[J]. Nature,2003,425(6953):90-93.

[35] CHO H,ZHAO X,HATORI M,et al. Regulation of circadian behaviour and metabolism by REV-ERB-alpha and REVERB-beta[J]. Nature,2012,485(7396):123-127.

[36] TAHARA Y,SHIBATA S. Circadian rhythms of liver physiology and disease:Experimental and clinical evidence[J]. Nat Rev Gastroenterol Hepatol,2016,13(4):217-226.

[37] LAMIA KA,PAPP SJ,YU RT,et al. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor[J]. Nature,2011,480(7378):552-556.

[38] SUN S,ZHOU L,YU Y,et al. Knocking down clock control gene CRY1 decreases adipogenesis via canonical Wnt/betacatenin signaling pathway[J]. Biochem Biophys Res Commun,2018,506(3):746-753.

[39] ZHANG EE,LIU Y,DENTIN R,et al. Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis[J]. Nat Med,2010,16(10):1152-1156.

[40] MARCHEVA B,RAMSEY KM,BUHR ED,et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes[J]. Nature,2010,466(7306):627-631.

[41] LAMIA KA,STORCH KF,WEITZ CJ. Physiological significance of a peripheral tissue circadian clock[J]. Proc Natl Acad Sci U S A,2008,105(39):15172-15177.

[42] JACOBI D,LIU S,BURKEWITZ K,et al. Hepatic bmal1 regulates rhythmic mitochondrial dynamics and promotes metabolic fitness[J]. Cell Metab,2015,22(4):709-720.

[43] DUMBELL R,MATVEEVA O,OSTER H. Circadian clocks,stress,and immunity[J]. Front Endocrinol(Lausanne),2016,7:37.

[44] ASTIZ M,OSTER H. Perinatal programming of circadian clock-stress crosstalk[J]. Neural Plast,2018,2018:5689165.

[45] YANG S,LIU A,WEIDENHAMMER A,et al. The role of m Per2clock gene in glucocorticoid and feeding rhythms[J]. Endocrinology,2009,150(5):2153-2160.

[46] RUTTER J,REICK M,WU LC,et al. Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors[J].Science,2001,293(5529):510-514.

[47] ASHER G,SCHIBLER U. Crosstalk between components of circadian and metabolic cycles in mammals[J]. Cell Metab,2011,13(2):125-137.

[48] KIL IS,LEE SK,RYU KW,et al. Feedback control of adrenal steroidogenesis via H2O2-dependent,reversible inactivation of peroxiredoxin III in mitochondria[J]. Mol Cell,2012,46(5):584-594.

[49] NEUFELD-COHEN A,ROBLES MS,AVIRAM R,et al. Circadian control of oscillations in mitochondrial rate-limiting enzymes and nutrient utilization by PERIOD proteins[J]. Proc Natl Acad Sci U S A,2016,113(12):e1673-e1682.

施引文献

资源附件(0)

访问统计