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Wednesday, July 18, 2018

In the liver’s secrets, new hope for medicine

From the Lab — The research: The mechanism through which the liver regulates fat secretion into the bloodstream

Written by Amitabh Sinha | Pune | Updated: June 19, 2018 1:00:54 am
In the liver’s secrets, new hope for medicine One of the several important functions performed by the liver is maintenance of an optimum level of fat in the human body.

The research: The mechanism through which the liver regulates fat secretion into the bloodstream
Researchers: Priyanka Rai, Mukesh Kumar, Roop Mallik & team
TIFR Mumbai; IISER Pune; IISc Bengaluru

One of the several important functions performed by the liver is maintenance of an optimum level of fat in the human body. Fats are energy-rich carbon compounds found in edible oily substances, and are a rich source of nutrients. After one eats, the fat in the food is absorbed in fatty tissues present in different parts of the body (e.g. hips). During this time, the energy comes from other easily broken-down ingredients of food like carbohydrates and glucose. In the absence of food for a long time, the fat is summoned for providing energy. These are first transported from fatty tissue to the liver, from where they enter the bloodstream at a controlled rate for distribution in the rest of the body.

An imbalance in the secretion of fat can lead to a variety of problems. Too much fat results in common diseases like diabetes or obesity. On the other hand, less than optimum secretion leads to an excess accumulation of fat in the liver, a condition known as fatty liver.

In the liver itself, the amount of fat stored varies with time. Relatively small amounts of fat make their way to the liver when food intake is happening at regular intervals. When intake does not happen for a long time, for example during night, this fat is summoned by brain signals to be processed and sent to the liver. Therefore, a far greater amount of fat goes into the liver in the absence of food intake for long hours, leading to massive increase of fat in liver.

During normal functioning, the liver secretes a controlled amount of fat, irrespective of the quantity it stores inside, so that the balance is always maintained. Scientists do not fully understand the mechanism that enables such control. New research by a team led by Roop Mallik in the Department of Biological Sciences at Tata Institute of Fundamental Research in Mumbai, with collaborators from IISER Pune and IISc Bangalore, has now come up with fresh insights on this.

The team’s experiments have shown how this fat is transported from within hepatocytes, the cells of the liver, to the outer boundary of these cells, from where it is secreted outside into the bloodstream. Their findings have been published in the US journal Proceedings of the National Academy of Sciences. This new insight not only helps understand the mechanism but also opens up the possibility of an outside intervention to keep the secretion of fat in balance.

Mallik’s laboratory at TIFR works on special kind of proteins called motor proteins, whose job is to transport material from one place to another inside cells. The researchers performed their experiments on rats to observe that micron-sized balls of fat were deposited inside the hepatocytes. In the ‘fed state’, that is when food intake was normal, about 10 to 20 balls of fat were seen in each cell. In the ‘fast state’, when the organism was without food for some time, this number could go up to hundreds in each cell.

A particular kind of motor protein found inside the liver, called kinesin, was seen transporting these fat balls from inside the hepatocyte to the outer boundary of the cell, from where the fat was being secreted outside.

The researchers noticed that when the organism was in the ‘fed state’, that is, when there were only between 10-20 fat balls in the hepatocytes, the transportation happened very efficiently. In the ‘fast state’, the rate of transportation fell significantly for the greater number of fat balls, so that overall rate of secretion of fat remained more or less constant. In the ‘fast state’, the motor protein kinesin was seen not to be binding to the fat balls as efficiently as it was doing in the ‘fed state’.

The scientists noticed that the ability of the kinesin protein to bind to the fat balls was being facilitated by insulin, the hormone. Insulin levels go up with food intake. This corresponds to a more efficient binding of kinesin protein with the fat balls in hepatocytes in the liver. During food intervals, the insulin levels go down and so does the ability of kinesin to bind with the fat balls.

The researchers’ findings could have important implications for maintaining fat balance inside human body and possibly in the treatment of obesity or diabetes. It opens up the possibility of delivering a drug-like molecule that mimics kinesin and binds with fat balls, thereby denying kinesin this opportunity. This can reduce the secretion of fat into the bloodstream. Scientists say such options could be explored in the future.

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