A fatty Rolex in the liver

5. July 2011
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The circadian clock controls our sleep and recovery times, performance and blood pressure. Even internal organs like the liver are working by a 24-hour clock. Studies now show how such a control mechanism functions and why disorders lead to fatty liver.

At some point always around midday we are plagued by hunger – even if a snack was eaten not so long ago. Yet, some resilient types survive long nights of partying without midnight ‘reinforcements’.

Why do most heart attacks and thromboses occur early in the morning? And why do shift workers sometimes have big problems with their digestion? These people add excess weight a lot more easily and their diabetes risk is higher.

DNA modification in day/night rhythm

Our body clock is largely daylight-controlled and is driven by a corresponding neuron-based clockwork in the suprachiasmatic nucleus (SCN) in the hypothalamus. Numerous studies and observations have shown that the activity of internal organs also are directed according to a 24-hour rhythm, even if they are not connected via appropriately-matched nerve connections to light-sensitive sensors.

The mechanisms which control the regularly-recurring activity and resting phases of the liver are described in an article in the scientific journal “Science” from a few weeks ago. According to these findings by Mitchell Lazar and his colleagues from the Institute for Diabetes, Obesity and Metabolism in Philadelphia (USA), modifications to the DNA are responsible for the rhythmic activity. The team was able to demonstrate in nocturnal mice that an appropriate enzyme, histone deacetylase, together with a cofactor, switches on thousands of genes at night and thus has effects on glucose and lipid metabolism. The findings also provide new insights into how the control center of circadian rhythms in the SCN is connected to the peripheral timing faculties.

Several thousand genes staying in time

The histone deacetylase 3 (HDAC3) plays a key role in the activation of genes. It removes acetyl groups from its target and thereby promotes linkage between histone and DNA. During the day, as the researchers found out, the enzyme is bound to approximately 14 000 sites in the genome of the mouse liver and at night only onto around 100. This was one difference that stunned the researchers themselves: “I was surprised by the breadth of the effect,” commented the head of the group, Lazar, on the data in a Radio Interview. “Hundreds of genes I would have expected, but not thousands.” This regular 24-hour cycle works even if the animals are kept in constant darkness, proof of the fact that their internal biological clock controls the activity of a myriad of genes.

If one switches the rhythm – in a way analogous to human jetlag – and sets feeding time to daylight hours, the HDAC3 activity also reverses. But the concentration of the enzyme in the liver cell remains over the course of 24 hours about the same. In order to bind to histones, this indirect DNA-blocker needs a corepressor (Rev Erbα) which appears in the diurnal rhythm and then disappears again. How much of this cofactor is available in the liver depends, however, not only on the nighttime activity of mice but also on glucose turnover and energy storage as fat. Regulatory mechanisms ensure that Rev Erbα is present again at the right time and stops fat synthesis.

Control deficiencies lead to fatty liver

If however HDAC3 and cofactor don’t turn up in accordance with the schedule, the enzymes remain active for the purpose of energy storage and fatty liver is the outcome. In an experiment, the researchers shut off HDAC3 in the liver for a few days. The triglyceride content increased thereafter almost by a factor of ten. Transaminase concentration in serum increased by contrast only slightly. Similar – though not as strong – effects resulted when the researchers saw to it that the co-factor was no longer available in the cell.

Our internal rhythms determine not only sleep, mood and activity of the liver, but also a multitude of other internal organs and metabolic processes. The blood sugar level also depends on the production of insulin from the pancreas, the level of which also swings up and down in the daily rhythm. If BMAL1 – another important factor in the internal clock – is switched off, lesions which may arise in the arterial wall after an injury are a lot more pronounced. In patients with metabolic syndrome, the nocturnal decline in blood pressure fails to take place. (“Nondippers“)

It’s known that whoever wakes up a sleeping person during certain stages of sleep alters their metabolism and therefore, for example, their glucose tolerance. Still, the connections from the SCN control center to the periphery are largely unknown. The researchers from Philadelphia show nonetheless at least how the body clock works in internal organs at the molecular level. Whether similar biochemical cogs work away in muscle, fat storage and other tissues is what the Lazar lab wants to find out in coming projects. It may perhaps be that someday jetlag and fatty liver disease in shift workers will be treated in a related manner.

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3 comments:

Dr Annah Patricia Hipona
Dr Annah Patricia Hipona

this is novel. this will help us manage our patient intelligently

#3 |
  0
Dr Annah Patricia Hipona
Dr Annah Patricia Hipona

this is a new thing, this will help us doctors managa our patients intelligently

#2 |
  0
Dr Gleb Barashkov
Dr Gleb Barashkov

Very interesting and important for undestanding correction of the metabolic problems. Thank you.

#1 |
  0
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