趙丹 葉樺
【摘要】非酒精性脂肪性肝?。∟AFLD)已發(fā)展為慢性肝病的主要病因,嚴(yán)重影響著公眾健康。NAFLD通常與肥胖癥及其并發(fā)癥相關(guān),但近幾年發(fā)現(xiàn)非肥胖性NAFLD患病率逐漸增加,這可能表明,除了肥胖、糖尿病、血脂異常等代謝因素外,其他因素也可能在脂肪肝的發(fā)展及其向NASH的發(fā)展過(guò)程中起重要作用。最近有研究表明睡眠及晝夜節(jié)律紊亂可通過(guò)干擾脂質(zhì)代謝、影響胰島素抵抗及腸道菌群等,從而在NAFLD發(fā)病機(jī)制中發(fā)揮重要作用。本文是對(duì)睡眠及晝夜節(jié)律與NAFLD關(guān)系的研究進(jìn)展進(jìn)行綜述。
【關(guān)鍵詞】非酒精性脂肪性肝病;睡眠;晝夜節(jié)律;代謝性疾病;生物鐘
基金項(xiàng)目:浙江省自然科學(xué)基金(LGF19H030006);寧波市自然科學(xué)基金(2019C50100)
1.NAFLD及其發(fā)病機(jī)制
非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)是指排除過(guò)量飲酒、病毒感染或其他肝臟疾病,以肝臟脂肪異常累積為特點(diǎn)的臨床病理綜合征。目前NAFLD全球發(fā)病率約為25%,亞洲地區(qū)則高達(dá)約29.6%。NAFLD涵蓋了從非酒精性單純性脂肪肝(NAFL)到非酒精性脂肪性肝炎(NASH)的廣泛范圍的肝損傷,部分NASH甚至更進(jìn)一步發(fā)展為肝硬化乃至肝細(xì)胞癌(HCC),其在美國(guó)等發(fā)達(dá)國(guó)家日益成為肝移植的指標(biāo)。
NAFLD與胰島素抵抗和遺傳易感性十分相關(guān),但其確切致病機(jī)制目前尚不清楚。1998年Day和James首次提出NAFLD發(fā)病機(jī)制的“二次打擊”學(xué)說(shuō)。該學(xué)說(shuō)認(rèn)為“初次打擊”是各種因素導(dǎo)致脂質(zhì)代謝紊亂,進(jìn)而促進(jìn)肝臟細(xì)胞脂肪變,其中心環(huán)節(jié)是胰島素抵抗(insulin resistance,IR)。其后的“二次打擊”是通過(guò)各類炎癥介質(zhì)造成肝損傷的過(guò)程。近年越來(lái)越多的研究更加支持“多重打擊”理論,即在具有遺傳傾向的個(gè)體中,炎癥的發(fā)生往往先于脂肪變性,炎癥可能與多種因素如氧化應(yīng)激、細(xì)胞因子的改變、游離脂肪酸(FFA)、內(nèi)質(zhì)網(wǎng)應(yīng)激(ERS)、肝臟脂毒性、鐵超載、腸道菌群失調(diào)、表觀遺傳、生活及飲食方式、睡眠與晝夜節(jié)律等共同促進(jìn)NASH的發(fā)生。
2.睡眠
睡眠占據(jù)了我們?nèi)祟惣s1/3的時(shí)間,對(duì)于人類的生活、工作及身體健康的重要性不言而喻?!?020-2021年中國(guó)睡眠指數(shù)報(bào)告》調(diào)查顯示在社會(huì)變遷、城市化發(fā)展、信息大爆炸及其他越來(lái)越多的因素影響下,國(guó)人的睡眠質(zhì)量不斷下降,睡得晚、睡得短、睡得淺成為國(guó)人睡眠的現(xiàn)實(shí)寫(xiě)照。
當(dāng)前睡眠不足與睡眠障礙已經(jīng)成為現(xiàn)代社會(huì)的常態(tài),且與2型糖尿病、心血管病、非酒精性脂肪性肝病及腫瘤等各類疾病的發(fā)生發(fā)展有密切的相關(guān)性。胰島素抵抗是公認(rèn)的代謝性疾病的重要環(huán)節(jié),而睡眠不足與睡眠障礙都會(huì)誘發(fā)葡萄糖耐受異常和胰島素抵抗。一項(xiàng)系統(tǒng)性回顧11項(xiàng)研究的Meta分析顯示,2型糖尿病的患病風(fēng)險(xiǎn)與睡眠時(shí)長(zhǎng)呈U型關(guān)系,短睡眠時(shí)長(zhǎng)與長(zhǎng)睡眠時(shí)長(zhǎng)都與2型糖尿病的患病風(fēng)險(xiǎn)增加顯著相關(guān)。韓國(guó)的一項(xiàng)人群追蹤調(diào)查發(fā)現(xiàn),與保持7小時(shí)睡眠的女性相比,睡眠時(shí)長(zhǎng)不足的女性發(fā)生高血壓的風(fēng)險(xiǎn)更高。Yazdanpanah 等在伊朗進(jìn)行的一項(xiàng)橫斷面研究,通過(guò)Framingham風(fēng)險(xiǎn)評(píng)分來(lái)預(yù)測(cè)心血管事件,發(fā)現(xiàn)睡眠少于6小時(shí)的受試者患心血管疾病的風(fēng)險(xiǎn)增加,且睡眠為8-8.9小時(shí)的受試者心肌梗死患病率最低。一項(xiàng)關(guān)于睡眠時(shí)間與癌癥特異性死亡率和全因死亡率的薈萃分析發(fā)現(xiàn),睡眠時(shí)間過(guò)長(zhǎng)會(huì)增加所有癌癥的特異性死亡率,同時(shí)乳腺癌患者的全因死亡率也會(huì)增加。睡眠改變?cè)谠S多常見(jiàn)的消化系統(tǒng)疾病中也發(fā)揮重要作用,例如非酒精性脂肪肝、胃食管反流病、腸易激綜合征和炎癥性腸病等。
3.睡眠與NAFLD
3.1睡眠不足
睡眠不足主要是由睡眠時(shí)間短和睡眠質(zhì)量不佳二者造成。Kim等人通過(guò)評(píng)估69463名中年工人及其配偶的睡眠時(shí)間,并通過(guò)收集生化、BMI等數(shù)據(jù),及通過(guò)B超判斷脂肪肝的存在,在控制相關(guān)混雜因素后發(fā)現(xiàn)睡眠時(shí)間短與NAFLD風(fēng)險(xiǎn)增加顯著相關(guān)。近年的幾項(xiàng)大數(shù)據(jù)人群研究也同樣發(fā)現(xiàn),睡眠時(shí)間短與NAFLD發(fā)病風(fēng)險(xiǎn)之間呈負(fù)相關(guān)性。日本的一項(xiàng)對(duì)12306名參與者進(jìn)行為期7年左右的隨訪研究,將參與者按睡眠時(shí)間分為4組:>7、6-7、5-6、≤5,發(fā)現(xiàn)與睡眠時(shí)間>7小時(shí)的人群相比,睡眠時(shí)間≤5小時(shí)是發(fā)生NAFLD的顯著風(fēng)險(xiǎn)因素。一項(xiàng)系統(tǒng)性回顧16項(xiàng)研究的Meta分析顯示,短睡眠時(shí)間(≤6h)不僅可增加NAFLD的發(fā)病風(fēng)險(xiǎn),且睡眠時(shí)間越短N(yùn)AFLD的患病率越高。然而也有其他研究顯示了不同結(jié)果,Chou等的研究認(rèn)為睡眠時(shí)間與NAFLD無(wú)獨(dú)立關(guān)系,甚至有研究認(rèn)為睡眠時(shí)間短可降低男性NAFLD發(fā)病的風(fēng)險(xiǎn)。
睡眠質(zhì)量不佳與NAFLD之間的相關(guān)性也已被證實(shí)。中國(guó)臺(tái)灣的一項(xiàng)隊(duì)列研究表明,在男性中睡眠質(zhì)量差與患NAFLD的風(fēng)險(xiǎn)增強(qiáng)有關(guān)。Takahashi等采用匹茲堡睡眠質(zhì)量指數(shù)(PSOI)對(duì)4828名受試者的睡眠情況進(jìn)行評(píng)價(jià),該研究發(fā)現(xiàn)睡眠質(zhì)量與NAFLD相關(guān),且存在性別差異。系統(tǒng)性回顧研究的一項(xiàng)Meta分析結(jié)果顯示,在女性中睡眠質(zhì)量差可能增加NAFLD發(fā)病風(fēng)險(xiǎn)。
基于這些研究,我們推斷睡眠不足導(dǎo)致NAFLD的發(fā)病機(jī)制有以下幾個(gè)可能。首先,白細(xì)胞介素-6(interleukin 6,IL-6)和腫瘤壞死因子α(tumor necrosis factor-α,TNF-α)等炎性細(xì)胞因子的參與是NAFLD發(fā)病機(jī)制的重要一環(huán),而已有研究證實(shí)睡眠不足會(huì)引起多個(gè)炎性細(xì)胞因子的改變。其次,睡眠不足會(huì)促使部分激素變化,進(jìn)而增加食欲,如胃饑餓素(ghrelin)水平升高和瘦素(leptin)水平降低。同時(shí)睡眠不足的人往往也會(huì)因?yàn)榉泵Φ纳罟?jié)奏或身體疲勞而減少日常鍛煉。第三,研究表明慢性睡眠不足會(huì)激動(dòng)下丘腦-垂體-腎上腺軸,升高血漿中皮質(zhì)類固醇的水平,進(jìn)而造成胰島素抵抗。此外,已知皮質(zhì)醇和其他糖皮質(zhì)激素可促進(jìn)外周脂肪組織的脂質(zhì)動(dòng)員,并促進(jìn)肝臟中的脂肪形成。
3.2過(guò)長(zhǎng)睡眠
雖然目前大多數(shù)研究都支持短睡眠時(shí)間與NAFLD患病率增加有相關(guān)性,但近幾年也有不少人群研究發(fā)現(xiàn),過(guò)長(zhǎng)睡眠才是導(dǎo)致NAFLD發(fā)生發(fā)展的又一因素。一項(xiàng)在韓國(guó)中年人中進(jìn)行的隊(duì)列研究(n=8841)發(fā)現(xiàn),在調(diào)整其他基本因素后,睡眠時(shí)間較長(zhǎng)組的NAFLD得分高于睡眠時(shí)間較短組的,這表明睡眠時(shí)間越長(zhǎng),NAFLD的發(fā)病率越高。在武漢進(jìn)行的一項(xiàng)研究,通過(guò)比較8965名不同睡眠時(shí)間的健康受試者在5年隨訪期間內(nèi)NAFLD的患病率,發(fā)現(xiàn)夜間睡眠時(shí)間短(<7小時(shí)/天)與NAFLD無(wú)明顯關(guān)聯(lián),而長(zhǎng)時(shí)間的夜間睡眠反而與NAFLD風(fēng)險(xiǎn)的適度增加有關(guān)。此外,也有相關(guān)的假說(shuō)支持這一結(jié)果??偰芰肯陌o息代謝率、體力活動(dòng)和飲食誘導(dǎo)的產(chǎn)熱,而已知睡眠時(shí)比清醒時(shí)消耗更少的能量,因此更有可能促進(jìn)NAFLD的形成。
3.3其他睡眠
白天午睡在亞洲地區(qū)是一種常見(jiàn)的社會(huì)現(xiàn)象,但在西方文化中卻很少見(jiàn)。迄今為止,人們對(duì)午睡與健康之間的影響知之甚少,尤其是對(duì)代謝性疾病。Ghazizadeh等在中東進(jìn)行的一項(xiàng)人群研究中,發(fā)現(xiàn)午睡與代謝綜合征存在著顯著的關(guān)聯(lián)。Peng等在上海市嘉定區(qū)進(jìn)行的研究發(fā)現(xiàn)在中老年人中白天午睡時(shí)間長(zhǎng)與患NAFLD的風(fēng)險(xiǎn)增加呈正相關(guān)。隨著快節(jié)奏的社會(huì)生活,工作日減少睡眠時(shí)間,而周末補(bǔ)覺(jué)越來(lái)越成為年輕人中的一種常態(tài)。Son等的研究表明,每天保持充足的睡眠時(shí)間有利于預(yù)防代謝性疾病,并發(fā)現(xiàn)在每天睡眠少于6小時(shí)的韓國(guó)成年人中,周末補(bǔ)覺(jué)與降低代謝綜合征患病率相關(guān)。
3.4阻塞性睡眠呼吸暫停綜合征(OSAHS)與NAFLD
阻塞性睡眠呼吸暫停綜合征(obsctructive sleep apnea hypopnea syndrome,OSAHS)是指在睡眠過(guò)程中由多種病因引起上呼吸道狹窄或阻塞塌陷,引起反復(fù)發(fā)生呼吸暫停及間歇低氧血癥,出現(xiàn)低氧血癥、高碳酸血癥、睡眠結(jié)構(gòu)紊亂及多系統(tǒng)損害的臨床綜合征。慢性間歇性低氧(intermittenthypoxia,IH)是OSAHS引發(fā)多器官病理改變的基礎(chǔ),長(zhǎng)期IH可導(dǎo)致慢性肝臟損害、炎癥反應(yīng)和纖維化的發(fā)生,從而導(dǎo)致NAFLD及NASH的發(fā)生發(fā)展。臨床上OSAHS患者與NAFLD常合并存在。肥胖與OSAHS密切相關(guān),肥胖人群中OSAHS患病率高達(dá)40%-60%,而在肥胖癥患者中NAFLD患病率為60%-90%。Ding等研究表明,單純鼾癥和輕、中、重度OSA組患者并發(fā)NAFLD的比例分別為37.21%、69.09%、68.34%、78.08%,且脂肪肝的程度與OSAHS的嚴(yán)重程度正相關(guān)。盡管現(xiàn)有的研究表明OSAHS對(duì)NAFLD的發(fā)生發(fā)展是有影響的,但目前仍缺乏足夠高質(zhì)量的臨床及動(dòng)物研究證明兩者之間相互作用的多重機(jī)制。
4.晝夜節(jié)律與NAFLD
地球繞太陽(yáng)進(jìn)行公轉(zhuǎn)形成光(晝)和暗(夜)之間的周期性改變,為了適應(yīng)這種環(huán)境變量,包括哺乳動(dòng)物在內(nèi)的大多數(shù)物種已經(jīng)進(jìn)化出一種稱為生物鐘(Circadian clock,CC)的近24小時(shí)內(nèi)源性計(jì)時(shí)裝置,是一種細(xì)胞自主的分子機(jī)制,在分子水平上也是有層次的運(yùn)行,細(xì)胞節(jié)律振蕩使大量時(shí)鐘基因有節(jié)律的表達(dá),導(dǎo)致機(jī)體生理和行為的明顯改變。
4.1 晝夜節(jié)律調(diào)節(jié)機(jī)制
晝夜節(jié)律主要是由視網(wǎng)膜神經(jīng)節(jié)細(xì)胞(retinal ganglion cells,RGC)檢測(cè)到的光引起的,由下丘腦視交叉上核的中央鐘驅(qū)動(dòng)。晝夜節(jié)律不局限于大腦,也存在于外周組織中,如脂肪組織、肝臟、腸道、免疫系統(tǒng)等。晝夜節(jié)律鐘的關(guān)鍵機(jī)制是轉(zhuǎn)錄-翻譯負(fù)反饋環(huán)路(transcription-translationfeedbackloops,TTFL),目前比較明確的反饋環(huán)路主要有兩條。其一,時(shí)鐘基因(Period,Per)和隱花色素基因(Cryptochrome,Cry)由CLOCK/BMAL1和NPAS2/BMAL1異二聚體激活并轉(zhuǎn)錄,其翻譯的PER和CRY蛋白進(jìn)入細(xì)胞核并抑制其自身的轉(zhuǎn)錄,然后新的晝夜節(jié)律周期再次開(kāi)始。其二,由核受體亞家族1D(nuclearreceptorsubfamily 1 group D member,NR1D,亦稱為REV-ERBα)與RAR相關(guān)的孤兒受體(RAR relatedorphanreceptor,RORα)家族組成,CLOCK/BMAL1異二聚體激活Rev-erbα和Rorα的轉(zhuǎn)錄,同時(shí)競(jìng)爭(zhēng)性與ROR反應(yīng)元件結(jié)合位點(diǎn)(RORE)結(jié)合,以調(diào)控BMAL1基因的節(jié)律性表達(dá)。REV-ERBα蛋白屬于負(fù)調(diào)控因子,與Bmal1啟動(dòng)子結(jié)合并抑制其轉(zhuǎn)錄,而RORα蛋白與啟動(dòng)子區(qū)域結(jié)合可促進(jìn)Bmal1的轉(zhuǎn)錄。最新研究發(fā)現(xiàn)的第三條自主反饋環(huán)路——DECs,其表達(dá)發(fā)揮了時(shí)鐘基因的功能,并且DECs可以通過(guò)與BMAL1結(jié)合或與CLOCK/BMAL1競(jìng)爭(zhēng)結(jié)合E-box位點(diǎn)來(lái)抑制其自身轉(zhuǎn)錄。通過(guò)以上這些各種分子構(gòu)成了完整的轉(zhuǎn)錄-翻譯負(fù)反饋環(huán)路,使生物體內(nèi)部環(huán)境與外部環(huán)境得以同步,維持正常的節(jié)律與功能。
4.2 晝夜節(jié)律與NAFLD
Turek等人首次發(fā)現(xiàn)晝夜節(jié)律基因突變的小鼠出現(xiàn)晝夜攝食節(jié)律紊亂,同時(shí)有高脂血癥、高瘦素血癥、肝脂肪變性、高血糖等改變。晝夜節(jié)律基因的缺失與肝臟脂肪變性的關(guān)系在多種小鼠模型中已得到證實(shí)。關(guān)于小鼠體內(nèi)CLOCK、BMAL1基因的研究發(fā)現(xiàn)其可以影響肝臟脂肪的合成、分解、儲(chǔ)存及利用。另外,REV-ERBα或HDAC3的缺失同樣也會(huì)導(dǎo)致高甘油三酯血癥和肝臟脂肪變性。在黑暗期,低濃度的REV-ERBα使HDAC3與肝臟代謝基因的關(guān)聯(lián)性降低,進(jìn)而更利于脂質(zhì)的生物合成和儲(chǔ)存;在光照期,高濃度的REV-ERBα增加了HDAC3與肝臟代謝基因的關(guān)聯(lián),從而減少了脂質(zhì)的生物合成。高脂飲食喂養(yǎng)下Cry基因缺乏小鼠相與正常小鼠相比更快且更容易出現(xiàn)肥胖,并且其脂質(zhì)代謝相關(guān)基因的表達(dá)上調(diào)。從上述的這些研究中不難發(fā)現(xiàn),晝夜節(jié)律基因是肝臟脂質(zhì)代謝的關(guān)鍵調(diào)節(jié)劑。因此機(jī)體一旦晝夜節(jié)律紊亂,必然導(dǎo)致肝臟脂質(zhì)代謝失調(diào),進(jìn)而加速NAFLD的發(fā)生發(fā)展。
5.總結(jié)
睡眠及晝夜節(jié)律改變可干擾脂質(zhì)代謝、影響胰島素抵抗及腸道菌群微生態(tài)等環(huán)節(jié),因此睡眠及晝夜節(jié)律紊亂在NAFLD的發(fā)生發(fā)展過(guò)程中扮演了重要的角色,但目前兩者之間確切的分子機(jī)制并不明確,仍需要更進(jìn)一步地探索??傊钊胩骄克呒皶円构?jié)律將為臨床充分認(rèn)識(shí)、診斷和治療NAFLD等代謝性疾病提供新的治療手段及思路。
參考文獻(xiàn):
[1]Estes Chris,Razavi Homie,Loomba Rohit et al. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease.[J] .Hepatology, 2018, 67: 123-133.
[2]Li Jie,Zou Biyao,Yeo Yee Hui et al. Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999-2019: a systematic review and meta-analysis.[J] .Lancet Gastroenterol Hepatol, 2019, 4: 389-398.
[3]Shingina Alexandra,DeWitt Peter E,Dodge Jennifer L et al. Future Trends in Demand for Liver Transplant: Birth Cohort Effects Among Patients With NASH and HCC.[J] .Transplantation, 2019, 103: 140-148.
[4]Day CP,James OF. Steatohepatitis: a tale of two " hits"〔J〕? Gastro- enterology,1998; 114( 4) : 842-5.
[5]Tilg Herbert,Adolph Timon E,Moschen Alexander R,Multiple Parallel Hits Hypothesis in NAFLD - Revisited After a Decade.[J] .Hepatology, 2020, undefined: undefined.
[6]中國(guó)睡眠質(zhì)量數(shù)據(jù)[J].中國(guó)科技信息,2020(24):6-9.
[7]Anothaisintawee Thunyarat,Reutrakul Sirimon,Van Cauter Eve et al. Sleep disturbances compared to traditional risk factors for diabetes development: Systematic review and meta-analysis.[J] .Sleep Med Rev, 2016, 30: 11-24.
[8]Shan Zhilei,Ma Hongfei,Xie Manling et al. Sleep duration and risk of type 2 diabetes: a meta-analysis of prospective studies.[J] .Diabetes Care, 2015, 38: 529-37.
[9]Kim Chan-Won,Chang Yoosoo,Kang Jeong-Gyu et al. Changes in sleep duration and subsequent risk of hypertension in healthy adults.[J] .Sleep, 2018, 41: undefined.
[10]Yazdanpanah Mohammad Hosein,Homayounfar Reza,Khademi Ali et al. Short sleep is associated with higher prevalence and increased predicted risk of cardiovascular diseases in an Iranian population: Fasa PERSIAN Cohort Study.[J] .Sci Rep, 2020, 10: 4608.
[11]Stone Chelsea R,Haig Tiffany R,F(xiàn)iest Kirsten M et al. The association between sleep duration and cancer-specific mortality: a systematic review and meta-analysis.[J] .Cancer Causes Control, 2019, 30: 501-525.
[12]Orr William C,F(xiàn)ass Ronnie,Sundaram Shikha S et al. The effect of sleep on gastrointestinal functioning in common digestive diseases.[J] .Lancet Gastroenterol Hepatol, 2020, 5: 616-624.
[13]Kim Chan-Won,Yun Kyung Eun,Jung Hyun-Suk et al. Sleep duration and quality in relation to non-alcoholic fatty liver disease in middle-aged workers and their spouses.[J] .J Hepatol, 2013, 59: 351-7.
[14]Wang Honglei,Gu Yeqing,Zheng Lixiao et al. Association between bedtime and the prevalence of newly diagnosed non-alcoholic fatty liver disease in adults.[J] .Liver Int, 2018, 38: 2277-2286.
[15]Peng Kui,Lin Lin,Wang Zhengyi et al. Short sleep duration and longer daytime napping are associated with non-alcoholic fatty liver disease in Chinese adults.[J] .J Diabetes, 2017, 9: 827-836.
[16]Okamura Takuro,Hashimoto Yoshitaka,Hamaguchi Masahide et al. Short sleep duration is a risk of incident nonalcoholic fatty liver disease: a population-based longitudinal study.[J] .J Gastrointestin Liver Dis, 2019, 28: 73-81.
[17]吳楚添,張晨星,肖琳,湯紹輝.睡眠時(shí)長(zhǎng)和睡眠質(zhì)量與非酒精性脂肪性肝病發(fā)病風(fēng)險(xiǎn)關(guān)系的Meta分析[J].中國(guó)全科醫(yī)學(xué),2020,23(36):4619-4625.
[18]Chou Yu-Tsung,Cheng Hsiang-Ju,Wu Jin-Shang et al. The association of sleep duration and sleep quality with non-alcoholic fatty liver disease in a Taiwanese population.[J] .Obes Res Clin Pract, 2018, 12: 500-505.
[19]Miyake Teruki,Kumagi Teru,F(xiàn)urukawa Shinya et al. Short sleep duration reduces the risk of nonalcoholic fatty liver disease onset in men: a community-based longitudinal cohort study.[J] .J Gastroenterol, 2015, 50: 583-9.
[20]Takahashi Atsushi,Anzai Yukio,Kuroda Masahito et al. Effects of sleep quality on non-alcoholic fatty liver disease: a cross-sectional survey.[J] .BMJ Open, 2020, 10: e039947.
[21]Gehrke Nadine,Schattenberg J?rn M,Metabolic Inflammation-A Role for Hepatic Inflammatory Pathways as Drivers of Comorbidities in Nonalcoholic Fatty Liver Disease?[J] .Gastroenterology, 2020, 158: 1929-1947.e6.
[22]Irwin Michael R,Olmstead Richard,Carroll Judith E,Sleep Disturbance, Sleep Duration, and Inflammation: A Systematic Review and Meta-Analysis of Cohort Studies and Experimental Sleep Deprivation.[J] .Biol Psychiatry, 2016, 80: 40-52.
[23]Lin Jianfei,Jiang Yanrui,Wang Guanghai et al. Associations of short sleep duration with appetite-regulating hormones and adipokines: A systematic review and meta-analysis.[J] .Obes Rev, 2020, 21: e13051.
[24]Rao Madhu N,Neylan Thomas C,Grunfeld Carl et al. Subchronic sleep restriction causes tissue-specific insulin resistance.[J] .J Clin Endocrinol Metab, 2015, 100: 1664-71.
[25]Peckett Ashley J,Wright David C,Riddell Michael C,The effects of glucocorticoids on adipose tissue lipid metabolism.[J] .Metabolism, 2011, 60: 1500-10.
[26]Kim Ji-Hye,Jung Dong-Hyuk,Kwon Yu-Jin et al. The impact of the sleep duration on NAFLD score in Korean middle-aged adults: a community-based cohort study.[J] .Sleep Med, 2019, 57: 144-150.
[27]Liu Cheng,Zhong Rong,Lou Jiao et al. Nighttime sleep duration and risk of nonalcoholic fatty liver disease: the Dongfeng-Tongji prospective study.[J] .Ann Med, 2016, 48: 468-476.
[28]Ekmekcioglu C,Touitou Y,Chronobiological aspects of food intake and metabolism and their relevance on energy balance and weight regulation.[J] .Obes Rev, 2011, 12: 14-25.
[29]Ghazizadeh Hamideh,Mobarra Naser,Esmaily Habibollah et al. The association between daily naps and metabolic syndrome: Evidence from a population-based study in the Middle-East.[J] .Sleep Health, 2020, 6: 684-689.
[30]Peng Kui,Lin Lin,Wang Zhengyi et al. Short sleep duration and longer daytime napping are associated with non-alcoholic fatty liver disease in Chinese adults.[J] .J Diabetes, 2017, 9: 827-836.
[31]Son Soo Min,Park Eun-Ju,Cho Young Hye et al. Association Between Weekend Catch-Up Sleep and Metabolic Syndrome with Sleep Restriction in Korean Adults: A Cross-Sectional Study Using KNHANES.[J] .Diabetes Metab Syndr Obes, 2020, 13: 1465-1471.
[32]Knaus Christoph, Diagnosis and Treatment of Obstructive Sleep Apnea Syndrome.[J] .Ther Umsch, 2016, 73: 209-12.
[33]Mesarwi Omar A,Loomba Rohit,Malhotra Atul,Obstructive Sleep Apnea, Hypoxia, and Nonalcoholic Fatty Liver Disease.[J] .Am J Respir Crit Care Med, 2019, 199: 830-841.
[34]Umbro Ilaria,F(xiàn)abiani Valerio,F(xiàn)abiani Mario et al. Association between non-alcoholic fatty liver disease and obstructive sleep apnea.[J] .World J Gastroenterol, 2020, 26: 2669-2681.
[35]Badran Mohammad,Ayas Najib,Laher Ismail,Insights into obstructive sleep apnea research.[J] .Sleep Med, 2014, 15: 485-95.
[36]Brunner Katherine T,Henneberg Cameron J,Wilechansky Robert M et al. Nonalcoholic Fatty Liver Disease and Obesity Treatment.[J] .Curr Obes Rep, 2019, 8: 220-228.
[37]Ding Haibo,Huang Jie-Feng,Xie Han-Sheng et al. The association between glycometabolism and nonalcoholic fatty liver disease in patients with obstructive sleep apnea.[J] .Sleep Breath, 2019, 23: 373-378.
[38]Evans Jennifer A,Collective timekeeping among cells of the master circadian clock.[J] .J Endocrinol, 2016, 230: R27-49.
[39]Wang Yan,He Yuqing,Su Chen et al. Nuclear Localized O-Fucosyltransferase SPY Facilitates PRR5 Proteolysis to Fine-Tune the Pace of Arabidopsis Circadian Clock.[J] .Mol Plant, 2020, 13: 446-458.
[40]Mukherji Atish,Dachraoui Mayssa,Baumert Thomas F,Perturbation of the circadian clock and pathogenesis of NAFLD.[J] .Metabolism, 2020, null: 154337.
[41]Schibler Ueli,Oxidation of CLOCK boosts circadian rhythms.[J] .Nat Cell Biol, 2019, 21: 1464-1465.
[42]Sato Trey K,Panda Satchidananda,Miraglia Loren J et al. A functional genomics strategy reveals Rora as a component of the mammalian circadian clock.[J] .Neuron, 2004, 43: 527-37.
[43]Sato Fuyuki,Kohsaka Akira,Bhawal Ujjal K et al. Potential Roles of Dec and Bmal1 Genes in Interconnecting Circadian Clock and Energy Metabolism.[J] .Int J Mol Sci, 2018, 19: undefined.
[44]Turek Fred W,Joshu Corinne,Kohsaka Akira et al. Obesity and metabolic syndrome in circadian Clock mutant mice.[J] .Science, 2005, 308: 1043-5.
[45]Pan Xiaoyue,Zhang Yuxia,Wang Li et al. Diurnal regulation of MTP and plasma triglyceride by CLOCK is mediated by SHP.[J] .Cell Metab, 2010, 12: 174-86. [58]
[46]Kumar Jha Pawan,Challet Etienne,Kalsbeek Andries,Circadian rhythms in glucose and lipid metabolism in nocturnal and diurnal mammals.[J] .Mol Cell Endocrinol, 2015, null: 74-88.
[47] Feng Dan,Liu Tao,Sun Zheng et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism.[J] .Science, 2011, 331: 1315-9.
[48]Barclay Johanna L,Shostak Anton,Leliavski Alexei et al. High-fat diet-induced hyperinsulinemia and tissue-specific insulin resistance in Cry-deficient mice.[J] .Am J Physiol Endocrinol Metab, 2013, 304: E1053-63.