Thursday, September 19, 2013

Alcohol throws off circadian clock to damage liver

Having evolved to keep time with our planet's rhythms – day and night, light and dark – we are wired at the genetic level to sleep at night and to wake and eat during the day. Research in recent years revealed that genetic and protein feedback loops – or clocks – operate in 24-hour cycles in every human cell. The clocks signal to thousands of genes, many of which speed up our ability to make and use energy from food during the day and turn it down at night.

Bucking those patterns – say by the working the night shift – has been shown to increase a person’s risk for heart disease, diabetes, cancer, depression, etc.

In a new twist, Shannon Bailey, Ph.D., associate professor in the Division of Molecular and Cellular Pathology within the UAB School of Medicine, just published a study that found chronic alcohol use may interfere with the genetic clocks in liver cells to accelerate liver damage. Dr. Bailey is a longtime liver disease expert with a new research focus on the role of circadian clocks in alcohol-related liver damage.

We thought to ask her whether too many martinis can throw off molecular clocks and, from a circadian point of view, what the healthiest hour is to drink a glass of wine.

Show notes for the podcast:

1:51 Genes are long chains of molecules that encode instructions for the building of the proteins, the workhorse molecules make up bodily structures and signals. Interestingly, the process of turning genes into proteins proceeds at a certain rate, so it has become the basis of a system that keeps time like a clock. To achieve a biochemical balance necessary for life, many genes are part of pathways that sense when there enough of any given protein, and sends signals to shut down the building process: so-called feedback loops. The twenty or so genes and proteins that make up the human circadian clock happen to perform these loops in a roughly 24-hour cycle, and so evolution favored them. Creatures that happened to align their metabolism to these clocks became one with their environment and were more likely to survive. Thus, the cells making up most life on earth today -- bacteria, plants, animals, etc. -- include genetic clocks.

3:44 In a larger sense, the clocks show the ability of genes to adjust their action in the face of changing environment. Genetic changes in energy use also occur after meals whenever they occur, and during the flight or fight response.

4:35 One of the functions of the circadian clocks in every human cell type is to turn off metabolic pathways that produce cellular energy from food when we don't need them. While obviously vital to life, highly active metabolic pathways create byproducts like free radicals that tear apart sensitive cell components and cause cells to self-destruct as part of many diseases, including major ones related to energetics: diabetes and heart disease. Shutting them down at night may help us to live longer.  

5:33  A major focus of Dr. Bailey's research is the mitochondria, sub-compartments of human cells that convert sugar from food into cellular energy by using oxygen.  She is especially interested in the role of mitochondria in liver disease. Overproduction of free radicals by mitochondria in liver cells damages other parts of the same cells, and shutting down these pathways at night may give cells a chance to repair the damage. A key emerging question is how not circadian clock genes in the nuclei of liver cells signal to mitochondria to control energy production.

6:39  While most studies look at the effect of staying up at night on circadian biology, Dr. Bailey wanted to look at the effect of alcohol on circadian clocks. Some of her interest stems from the fact that neuroscientists have been exploring in recent years whether or not circadian clocks in nerve cells in the brain may contribute to the forming of addictions. Up until the current study, only a few studies had looked at the effect of alcohol consumption on peripheral cells (gut, heart, liver, etc.). It's really starting to take off, says Dr. Gohlke.

8:43 As whole, the body’s circadian clock is regulated by a part of the brain called the suprachiasmatic nucleus, which drives daily physiological and behavioral rhythms. The newest frontier, embodied by Dr. Bailey’s study, is the effort to understand the role of the circadian clock in each cell type, and what happens when the cell-specific clocks are out of sync with the central clock in the brain. The liver is the organ in the body most responsible for regulating system-wide energy needs and is charged with holding steady levels of sugar supplied to cells by the bloodstream. Studies have shown that molecular clocks in the liver help keep the blood sugar level constant as we eat and fast, sleep and wake., largely through adjusting levels of the hormone insulin. If we throw the clocks off, we throw our blood sugar off and contribute to the development of diabetes.

9:54  The liver also plays a prominent role in the amount of cholesterol and fat in the blood, as well as the breakdown of drugs in the bloodstream.  Should the clocks be shown to regulate those pathways and alcohol affects them, then chronic drinking hardens arteries, the leading cause of heart attacks and strokes, and contributes to obesity.

10:32 To study the effect of alcohol on circadian clocks, Dr. Bailey and her team separated mice into two groups, one that received a healthy diet, and a second that had the same diet plus a steady supply of alcohol (ethanol). They then collected brain and liver samples for both mice to look for changes in clock genes patterns. They found that expression of metabolic genes that normally up and down  in 24 hours cycles no longer do so with chronic alcohol use. It also looked like metabolic pathways that normally operate in sync became disjointed.

13:35 In a healthy individual, certain clock genes in liver cells are expressed three hours after the same genes are expressed in the brain. One theory holds that the time lapse is a temporal signal between the systems that monitor how much energy we need, and those that supply the right amount of energy in response.  If alcohol throws off the liver cell clocks, they may no longer proceed in sync with the brain clock. Such a loss of synchrony represents a potential disease mechanism in heart disease, diabetes and obesity.

15:56 Fatty liver disease, which is very common in the United States, is the earliest stage in the progression toward much more serious liver diseases like cirrhosis. It is also seen people in pre-diabetes or obesity. Healthy people store their fat in their fat cells, their adipose tissue, and not their liver cells. Dr. Bailey is interested in whether or not disruption of liver clocks contributes to this build up of fat in liver cells.

17:31 As the understanding of molecular clocks grows, researchers will seek to influences parts of the clock that contribute to disease. Research teams have already shown that some drugs, at least in animal models, can fine-tune clocks to counter weight gain. Dr. Baily is looking forward to testing whether such drugs can counter the contribution of clock genes, under the action of alcohol, to liver damage

18:03 Dr. Bailey's study did look at whether the expression of proteins that break down alcohol fluctuate with time of day, but not at how active those proteins are. She has proposed a series of studies that will seek to determine what time of day is best for that glass of wine. The studies so far at least suggest that there may be times of day when the liver is more or less vulnerable to the toxic effects of alcohol.

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