A multi–disciplinary team of researchers from the Mechanobiology Institute, Singapore (MBI) at the National University of Singapore (NUS), the Institute of Bioengineering and Nanotechnology (IBN) of A*STAR, and BioSyM, Singapore–MIT Alliance for Research and Technology have described the mechanical principles adopted by liver cells as they remove excess bile during obstructive cholestasis.

This study was published online in the Journal of Hepatology.

The research team comprises team leader Professor Hanry Yu, who is a Principal Investigator at MBI and IBN; Mr Kapish Gupta, who is a graduate student at MBI and first author of the paper; as well as their fellow MBI researchers – Associate Professor Virgile Viasnoff, Associate Professor Low Boon Chuan, and Assistant Professor Pakorn (Tony) Kanchanawong.

Research conducted at MBI revealed how liver cells already possess the ability to eliminate excess bile from tubes located inside the liver, which feed bile into the biliary ducts.

The key to the liver’s ability to eliminate excess bile is the fact that the ‘tubes’ through which bile enters the biliary tract are not merely a set of inactive pipes, but are actually hollow spaces between living cells. The walls of the tubes are essentially the outside surfaces of the cells.

The research team used an artificial culture system, which allowed the easy manipulation of cultured liver cells. They then used high–end imaging techniques to visualise the dynamics of the tubes that develop within this culture system.

The team sought to investigate the response of the cells that line a blocked bile duct by obstructing the bile tract artificially and observing what happened. What they found was that as the bile accumulated behind the blockage, the tube began to swell or bulge, and this put pressure on the cells that make up the wall of the tube.

The key to the removal of excess bile lies in the internal structure of the cell itself. Immediately adjacent to the cell membrane is a network of protein cables or filaments known as the actin cortex. This structure serves to strengthen the cell, and help it retain its shape and integrity even when external forces are applied to the cell surface – external forces like the increased pressure from a build–up of fluid. Normally the actin cortex is able to counter the forces applied to it, and even when some damage to the network is incurred, it is quickly fixed by proteins that can reassemble the actin filaments.

However, when the pressure becomes too great, the actin cortex will rupture, and it will not be repaired. Although the bile cannot simply pass through the membrane, it can, as the researchers discovered, push the membrane into the cell, through the gap in the ruptured actin cortex. As this occurs a bubble–like vesicle forms inside the cell, and it is inside this vesicle that the bile enters and passes through the cell. The bile is essentially packaged inside these vesicles for its transport through the cell, and away from the site where it had accumulated.

Although the liver does not stop producing bile even when the biliary ducts are blocked, it is now evident that the liver does have a process in place to look after itself when a potentially damaging amount of bile builds up inside a blocked duct.

As the researchers showed, the rate of vesicle formation, and hence the uptake of excess bile into liver cells, can indeed be adjusted using drugs, at least in the cell culture setting. Improving the effectiveness of this naturally occurring mechanism, by increasing, for example, the rate of vesicle formation, may indeed encourage bile elimination from the blocked duct so as to avoid long–term liver damage and increase the effectiveness of surgical intervention.