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A Molecular Link Between Sleep and Liver Fat

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

Scientists 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.

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 ×îÐÂÂ鶹ÊÓƵ 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.