Is your work schedule destroying your liver?

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They may not do their own grocery shopping, wear makeup, or do their taxes, but there's no denying that proteins, just like us, do go to work in shifts. Health problems come up when our day and night shifts clash with what our proteins are programmed to do.

Many of our bodies' proteins are expected to show up every day at specific times and locations to carry out important metabolic processes in a diurnal cycle commonly known as a circadian rhythm. The temporal-precision of our bodies' biochemical machines results in a cellular cycle, wherein the proteins in some of our cells work a "day shift," and others a "night shift," clocking in and out in coordination with daily cycles of light and nutrient availability.

The liver repair team works the day shift

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 identified several key molecules involved in the circadian rhythm that controls the daily cycle of fat production and storage in the livers of mice. Their findings, which are published in the March 11th issue of Science, reveal that the protein histone deacetylase 3 (HDAC3) is recruited once a day to thousands of specific locations in the liver genome by the nuclear receptor protein known as Rev-erbα.


Once HDAC3 has arrived at the specified locations in the liver genome, it works in concert with Rev-erbα to suppress the expression of genes involved in the liver's production of fat. HDAC3 accomplishes this by physically reconfiguring how the DNA is packed into chromosomes, making the genetic data the DNA encodes either more or less accessible to other regulatory molecules that are responsible for transcribing the data.

To demonstrate the time-specific recruitment of HDAC3 to liver metabolic genes, Dr. Lazar's research team sequenced the DNA associated with HDAC3 in the liver at different time points throughout the day. When DNA associated with HDAC3 in the liver was searched in the morning, HDAC3 was bound to just 120 sites in the DNA. Searching the DNA 12 hours later, however, revealed a dramatic increase in HDAC3 binding sites, which had increased to over 14,000 sites by day's end.


Sticking with our blue collar protein analogy, these findings demonstrate that HDAC3 shows up to work in the liver genome during the day to suppress fat production, and clocks out at night to allow fat production to increase; In Dr. Lazar's words, "this work shows that the epigenome, which is critical for regulating how genes are expressed, undergoes reversible remodeling every day."


Circadian misalignment

This image is taken from the research paper, and illustrates the importance of HDAC3 in the regulation of fat production in the liver. When the livers of mice were deprived of HDAC3 for just 2 weeks, staining for neutral lipid indicated that they accumulated an unhealthy amount of fat (fat is stained red in the top image). The bottom image, which is also stained for neutral lipid, is representative of a liver with normal HDAC3 and fat levels.


Problems can arise when the work schedules of our bodies' molecular employees clash with the schedules of our bodies themselves, that is to say our own schedules. The findings by Dr. Lazar and his colleagues help shed light on the long-recognized but poorly understood link between the health complications of individuals employed in shift work and the odd hours that they're employed.

As Dr. Lazar explains, the daily recruitment and dismissal of HDAC3 from the liver genome "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." For example, when we eat at an abnormal time of day (think midnight snack), pull an all-nighter, or take a trans-continental flight, our behavior is clashing with the regimented processes of various metabolic organs. When the body is at odds with itself like this, it is said to be in circadian misalignment.


Prolonged circadian misalignment has been linked to serious metabolic dysfunction and a slew of adverse health effects, most notably in individuals employed in shift work, who exhibit an elevated incidence of disorders like obesity, diabetes, and heart disease; for many nurses, firemen, and others who work unconventional hours, their occupation has been shown to be an occupational hazard in and of itself.

Dr. Lazar and his colleagues intend to continue their investigation of circadian rhythms in other tissues, and extend their research so as to consider the pathological implications of their findings. With any luck, continued investigation into the molecular underpinnings of circadian rhythms by laboratories like Dr. Lazar's will help us better understand conditions involving mismanaged fat production and storage—such as metabolic syndrome and diabetes—while continuing to shed light on how we might avoid killing ourselves at our odd-hour jobs.


Research Published in Science
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