NIH Research Matters

liver411

March 21, 2011
A Molecular Link Between Sleep and Liver FatScientists have discovered a molecular link between the body's biological clock and fat production in the liver. The finding may help explain why disrupting daily cycles, such as rotating shift work, increases the risk of diseases like obesity and diabetes.
Depletion of liver HDAC3 causes fatty liver in normal adult mice. Above is liver tissue lacking HDAC3 (fat is stained red). Below is liver with normal HDAC3 levels. Source: Zheng Sun, Ph.D.; University of Pennsylvania School of Medicine.

Depletion of liver HDAC3 causes fatty liver in normal adult mice. Above is liver tissue lacking HDAC3 (fat is stained red). Below is liver with normal HDAC3 levels. Source: Zheng Sun, Ph.D.; University of Pennsylvania School of Medicine.


Mammals—and many other organisms—have natural daily rhythms. In people, the brain's master clock sends out signals to other brain regions to make hormones that help keep you awake during the day. In the evening, when less light enters your eyes, the master clock triggers production of a hormone that makes you feel drowsy and helps you stay asleep. This daily cycle, called the circadian rhythm, affects various body functions, including body temperature, eating habits and blood pressure. Jetting across time zones or working the night shift causes disruptions in this rhythm.
As many as 1 in 4 Americans are estimated to have excess liver fat, which can lead to inflammation and damage that could eventually cause liver failure. Fat production in the liver is known to be affected by circadian rhythms. Past studies have shown that disrupting circadian rhythms in mice causes the animals to develop excess liver fat. They also suffer from obesity, diabetes and metabolic syndrome. A team led by Dr. Mitchell A. Lazar of the University of Pennsylvania set out to understand the molecular connections between circadian rhythm and fat production in the mouse liver.
Researchers have found that liver cells undergo epigenetic modifications that vary with the time of day. Epigenetic modifications don’t alter DNA sequences but do influence gene expression. A process called histone acetylation, involving the protein histone deacetylase 3 (HDAC3), is thought to play a role in how the circadian clock affects gene expression in the liver. Lazar and his colleagues set out to examine which genes were bound by HDAC3 in the mouse liver at different times of day. Their work, funded by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), appeared in the March 11, 2011, edition of Science.
The researchers found that during the day, when mice are typically inactive or asleep, HDAC3 binds to over 14,000 sites in the mouse liver genome. At night, when mice are active, HDAC3 nearly vanishes from the genome. The scientists noticed that the amount of rev-erbα, which acts as a gene repressor and is known to be a component of the circadian clock, oscillated along with HDAC3 binding to the genome. Experiments revealed that the genomic binding sites of the 2 proteins significantly overlap.
Many of these genomic sites include genes involved in fat production. The researchers found that when HDAC3 and rev-erbα are bound to the genome, expression of these genes is reduced. This suggests that during the day, when mice are asleep and fasting, HDAC3 and rev-erbα help prevent the liver from producing fat. As predicted, when either protein was removed from the mouse liver, the fat metabolism genes became active regardless of time or activity level. This led to a rapid buildup of fat in the liver.
The findings may help explain what goes wrong with fat production and storage to cause conditions such as metabolic syndrome, insulin resistance and diabetes. "This may explain in part why altered circadian rhythms in people who do shift work is associated with metabolic disorders," Lazar says. The researchers are now studying these molecules in other tissues as well.
—by Amy Alabaster and Harrison Wein, Ph.D.

lin12345

411老师也不翻译一下 真懒

lin12345

2011年3月21日,

一种分子之间的联系、睡眠和肝FatScientists已经发现一种分子之间的联系,身体的生物钟生产在肝脏和脂肪。这个发现可能有助于解释为什么破坏日常周期,如旋转变换工作的疾病的风险,增加了如肥胖和糖尿病。

肝HDAC3损耗原因在正常成年鼠脂肪肝。以上是由于缺乏HDAC3肝组织(脂肪弄脏了红色)。下面是HDAC3肝脏正常水平。资料来源:郑的太阳,博士,宾夕凡尼亚州州立大学医学院。



肝HDAC3损耗原因在正常成年鼠脂肪肝。以上是由于缺乏HDAC3肝组织(脂肪弄脏了红色)。下面是HDAC3肝脏正常水平。资料来源:郑的太阳,博士,宾夕凡尼亚州州立大学医学院。许多其他的organisms-have Mammals-and自然每天的时间节奏。在人们,大脑的主人钟发出信号给其他脑区,使的荷尔蒙分泌,帮助保持清醒,你在白天。在晚上,当较少的光进入你的眼睛,主人钟引发生产的激素,它使你觉得昏昏欲睡,并帮助你停留在睡觉。这日循环,叫做生理节奏,影响人体多种功能,包括体温、饮食习惯、和血压。喷射到另外的时区或做夜班导致中断在这个节奏。

多达1 / 4的美国人估计有多余的肝脂肪,它可以导致炎症和损伤可能会最终导致肝功能衰竭。生产的肝内脂肪是已知的受影响的生理节律。过去的研究已经表明,破坏原因的昼夜节律在小鼠体内的肝脂肪过量动物发展。他们也会患上肥胖症、糖尿病和代谢综合症。米切尔博士领导的小组由A拉撒尔宾州大学的出发去理解分子之间联系的生理节奏和脂肪产量在小鼠肝脏。

研究人员发现肝脏干细胞分化的表观遗传修改,随白天的时间。表观遗传修改不改变DNA序列,但确实影响基因的表现。这个过程称为组蛋白去乙酰化,包括蛋白质组蛋白3(HDAC3 deacetylase),被认为是发挥了作用,在如何影响基因表达的生物钟在肝脏。拉撒尔和他的同事们着手调查哪些基因受到HDAC3在小鼠肝脏在不同时期的日子。他们的工作,经费由国家卫生研究院的国家研究所的糖尿病、消化及肾脏疾病(NIDDK),出现在3月11日,2011年版的科学。

研究人员发现,在白天,当老鼠通常无效或睡着了,HDAC3裹1400万个地点的小鼠肝脏的基因组。在晚上,当老鼠是活跃的,HDAC3几乎消失在基因组中。科学家们注意到,rev-erbα的数量,它能起到一种抑制基因,是一种已知的组成部分,体内的生理时钟,彷徨随着HDAC3绑定到基因组。实验显示,前两年的基因组结合位点的蛋白质明显重叠。

许多这些基因组的地点包括基因涉及脂肪生产。研究人员发现,当HDAC3和rev-erbα绑定到基因组中,这些基因表达的减少。这表明,在白天,当老鼠睡着了,禁食的时候,HDAC3和rev-erbα有助于防止肝脏产生的脂肪。正如所预测的,当也蛋白质被清除出了小鼠肝脏,脂肪代谢基因变得活跃的时间或活动不论水平。这导致了一种快速积聚的脂肪在肝。

这些发现可能有助于解释与脂肪到底哪里出了问题,导致生产、储存条件如代谢综合征、胰岛素抵抗和糖尿病。“这也许可以解释为什么在部分人昼夜节律的改变轮班工作的伴随代谢障碍、“拉撒尔说。研究者正在研究这些分子在其他组织的损伤。

艾米雪花石膏和哈里森则存在的运输研究所硕士论文。

hatecccdna

简言之就是在睡眠的时候能够产生HDAC3和rev-erbα并且抑制肝脏脂肪产生。
对我们战友的意义是，大家要注意休息，注意睡眠。