Chronic ethanol consumption disrupts the core molecular clock and diurnal rhythms of metabolic genes in the liver without affecting the suprachiasmatic nucleus.
Chronic ethanol consumption disrupts the core molecular clock and diurnal rhythms of metabolic genes in the liver without affecting the suprachiasmatic nucleus.
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DOI：
10.1371/journal.pone.0071684
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Bailey SM
中科院分区：
文献类型：
--
作者：
Filiano AN;Millender-Swain T;Johnson R Jr;Young ME;Gamble KL;Bailey SM
慢性酒精摄入扰乱了多种代谢途径，包括β氧化和脂质生物合成，促进了酒精性脂肪性肝病的发展。这些代谢途径中的许多都是由细胞自主的生物钟直接调节的，最近的研究表明，日常代谢节奏的中断导致了多种常见的心脏代谢性疾病(包括非酒精性脂肪性肝病)。然而，目前尚不清楚乙醇是否会扰乱肝脏的核心分子时钟，也不知道这是否会反过来改变脂质代谢的节奏。在这里，我们测试了这样的假设，即慢性酒精摄入扰乱了肝脏的分子生物钟，并潜在地改变了脂代谢基因的日常表达模式。与之前的研究一致，喂食含酒精饮食的雄性C57BL/6J小鼠显示出比对照组小鼠更高的肝脏甘油三酯水平，这表明肝脏脂肪变性。此外，在酒精喂养的小鼠的肝脏中，核心时钟基因(BMal1、Clock、Cry1、Cry2、per1和per2)和时钟控制基因(dBP、hlf、nocturin、Npas2、rev-erbα和tef)的昼夜振荡发生了改变。相比之下，乙醇对视交叉上核(SCN)核心时钟基因的表达影响较小。这些结果在Per2Luciferase敲入小鼠中得到了证实，在小鼠中，乙醇诱导了肝脏中PER2：：Luc生物发光振荡的时相提前，但不能诱导SCN。此外，在酒精喂养的小鼠的肝脏中，PER2：：LUC振荡的阶段有更大的变异性。酒精摄入还影响C57BL/6J小鼠肝脏代谢基因Adh1、CPT1a、CYP2E1、Pock1、Pdk4、Ppargc1a、Ppargc1b和Srebp1c的昼夜振荡。总而言之，长期摄入酒精会改变肝脏生物钟的功能。重要的是，这些结果表明，慢性酒精摄入足以导致脂肪变性的水平，扰乱了核心肝脏时钟以及关键脂肪代谢基因的昼夜节律。
Chronic ethanol consumption disrupts several metabolic pathways including β-oxidation and lipid biosynthesis, facilitating the development of alcoholic fatty liver disease. Many of these same metabolic pathways are directly regulated by cell autonomous circadian clocks, and recent studies suggest that disruption of daily rhythms in metabolism contributes to multiple common cardiometabolic diseases (including non-alcoholic fatty liver disease). However, it is not known whether ethanol disrupts the core molecular clock in the liver, nor whether this, in turn, alters rhythms in lipid metabolism. Herein, we tested the hypothesis that chronic ethanol consumption disrupts the molecular circadian clock in the liver and potentially changes the diurnal expression patterns of lipid metabolism genes. Consistent with previous studies, male C57BL/6J mice fed an ethanol-containing diet exhibited higher levels of liver triglycerides compared to control mice, indicating hepatic steatosis. Further, the diurnal oscillations of core clock genes (Bmal1, Clock, Cry1, Cry2, Per1, and Per2) and clock-controlled genes (Dbp, Hlf, Nocturnin, Npas2, Rev-erbα, and Tef) were altered in livers from ethanol-fed mice. In contrast, ethanol had only minor effects on the expression of core clock genes in the suprachiasmatic nucleus (SCN). These results were confirmed in Per2Luciferase knock-in mice, in which ethanol induced a phase advance in PER2::LUC bioluminescence oscillations in liver, but not SCN. Further, there was greater variability in the phase of PER2::LUC oscillations in livers from ethanol-fed mice. Ethanol consumption also affected the diurnal oscillations of metabolic genes, including Adh1, Cpt1a, Cyp2e1, Pck1, Pdk4, Ppargc1a, Ppargc1b and Srebp1c, in the livers of C57BL/6J mice. In summary, chronic ethanol consumption alters the function of the circadian clock in liver. Importantly, these results suggest that chronic ethanol consumption, at levels sufficient to cause steatosis, disrupts the core hepatic clock as well as the diurnal rhythms of key lipid metabolism genes.
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影响因子：
20.1
作者：
Durgan DJ;Pulinilkunnil T;Villegas-Montoya C;Garvey ME;Frangogiannis NG;Michael LH;Chow CW;Dyck JR;Young ME
通讯作者：
Young ME
DOI：
10.1016/j.bbrc.2009.01.150
发表时间：
2009-03-13
影响因子：
3.1
作者：
Ando, Hitoshi;Takamura, Toshinari;Kaneko, Shuichi
通讯作者：
Kaneko, Shuichi
影响因子：
4.7
作者：
Chen, CP;Kuhn, P;Sarkar, DK
通讯作者：
Sarkar, DK
酒精性肝病：发病机制和新的治疗靶点。
影响因子：
29.4
作者：
Gao B;Bataller R
通讯作者：
Bataller R
DOI：
10.1111/j.1530-0277.2011.01483.x
发表时间：
2011-08
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Brager AJ;Ruby CL;Prosser RA;Glass JD
通讯作者：
Glass JD