Web address:
http://www.sciencedaily.com/releases/2011/03/
110310141418.htm
Molecules Work the Day Shift to Protect the Liver from Accumulating
ScienceDaily (Mar. 10, 2011) The liver normally makes and stores fat, which
is required in moderation for normal body function. However, if the process
goes awry, excess fat in the liver can cause major liver damage. In fact, fatty
liver is a leading cause of liver failure in the United States, and is often
brought on by obesity and diabetes. In turn, the increasing prevalence of these
diseases has brought with it an epidemic of liver disease.
Abnormal sleep patterns, such as those of shift-workers, can be risk factors
for obesity and diabetes. Investigators have known for decades that fat
production by the liver runs on a 24-hour cycle, the circadian rhythm, and is
similar to the sleep-wake cycle. A research team led by Mitchell Lazar, MD,
PhD, director of the Institute for Diabetes, Obesity, and Metabolism at the
University of Pennsylvania School of Medicine, has discovered molecules that
act as "shift workers" to maintain the daily rhythm of fat metabolism. When
those molecules do not do their jobs, the liver dramatically fills with fat.
These findings are reported in this week's issue of Science.
Lazar and his colleagues, including Cell and Molecular Biology graduate student
Dan Feng, found a team of molecules that, in normal mice, migrates to the
genome of liver cells during the daytime. One of the team members, a protein
called Rev-erb, delivers the molecular workers to thousands of specific
locations in the liver genome, many of which are near genes involved in the
production of fat. Another team member, called histone deacetylase 3 (HDAC3),
does construction work on the protein scaffold (the epigenome) surrounding the
genome to dampen the activity of the fat-related genes.
"This work shows that the epigenome, which is critical for regulating how genes
are expressed, undergoes reversible remodeling every day," said Lazar. "This
leads to a circadian rhythm of metabolism that is important, because disruption
of this rhythm leads to fatty liver. This may explain in part why altered
circadian rhythms in people who do shift work is associated with metabolic
disorders."
Histones are proteins found in the nucleus that package and order DNA into
structural units. Changes to these epigenetic structures alter how DNA folds in
chromosomes, making genes less or more accessible to regulatory proteins and
enzymes that copy genes into RNA messages.
Construction Team
During the night, the day shift molecules depart the liver genome, and fat
production increases due to other regulatory molecules. The fat production is
kept in check when the Rev-erb construction team returns to the genome the next
day. However, if either Rev-erb or HDAC3 is prevented from doing its job, the
cycles do not occur, and the liver fills with fat.
By sequencing the DNA associated with HDAC-3 in the liver the Penn team found
HDAC in 100 places in the liver genome at 5:00am, but 12 hours later at 5:00pm,
HDAC was present in 15,000 places in the liver genome, indicating that it had
been brought to the liver during the day. They also found that Rev-erb follows
the same daily pattern, because it is the protein that gives HDAC-3 a ride to
work.
The Lazar lab is looking in other tissues -- fat cells, muscle, for example --
to see if the same team of molecules is at work, as well as delving deeper into
human applications to see how the findings may help explain what goes wrong
with fat production and storage in conditions such as metabolic syndrome,
insulin resistance, and diabetes. These findings also raise the interesting
question of whether certain drugs should be given at specific times of day, to
have greater benefit with reduced side-effects.
In addition to Lazar and Feng, Penn co-authors are Zheng Sun, Shannon Mullican,
and Theresa Alenghat. The study was a collaboration with Tao Liu and X. Shirley
Liu, at the Dana-Farber Cancer Institute in Boston. The National Institute of
Diabetes, Digestive, and Kidney Diseases provided funding for this research.
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Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily
staff) from materials provided by University of Pennsylvania School of Medicine.
Journal Reference:
1. Dan Feng, Tao Liu, Zheng Sun, Anne Bugge, Shannon E. Mullican, Theresa
Alenghat, X. Shirley Liu, and Mitchell A. Lazar. A Circadian Rhythm
Orchestrated by Histone Deacetylase 3 Controls Hepatic Lipid Metabolism.
Science, 11 March 2011: 1315-1319. DOI: 10.1126/science.1198125
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University of Pennsylvania School of Medicine (2011, March 10). Molecules work
the day shift to protect the liver from accumulating fat. ScienceDaily.
Retrieved March 13, 2011, from http://www.sciencedaily.com
/releases/2011/03/110310141418.htm
Note: If no author is given, the source is cited instead.
Disclaimer: This article is not intended to provide medical advice, diagnosis
or treatment. Views expressed here do not necessarily reflect those of
ScienceDaily or its staff.
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