Gene Controls Whether Liver Cells Double Or Die

A molecule called YAP regulates the size of the liver by determining whether liver cells proliferate or die in response to damage.

AsianScientist (Aug. 14, 2017) – Researchers at Tokyo Medical and Dental University (TMDU) have identified a molecule called YAP that controls the regenerative properties of the liver. Their findings, published in the journal Nature Communications, could be useful in explaining the causes of liver diseases associated with dysregulation of liver functions.

For organs to maintain a steady state and fulfill their intended functions, the rates at which the cells within them multiply or die off need to be equal. This balance must also be adjusted when events such as an injury or infection occur.

However, the mechanisms to achieve this balance have remained obscure, including for the liver, which is particularly vulnerable to destabilization owing to its function in detoxifying the body.

In this study, a research team led by Professor Hiroshi Nishina at TMDU showed that a molecule called YAP regulates the fate of liver cells called hepatocytes, determining whether they proliferate to boost the organ’s bulk or are degraded and removed.

The team used a range of different techniques to introduce different variants of the YAP gene into mouse liver. Earlier findings had determined that an activated form of YAP normally enters the nucleus of liver cells where it promotes the expression of genes that cause these cells to proliferate.

But when the TMDU researchers introduced YAP into liver cells, the effects on cell fate differed, depending on whether a hydraulic pressure or a virus carrier was used. They realized that the difference was due to injury caused by hydraulic pressure.

“Once we suspected that cell injury was a key factor in determining the effect of YAP on liver cells, we analyzed which type of liver injury caused YAP to induce cells to be eliminated rather than multiply,” said Nishina. “Using toxic chemicals that damage only specific liver cell types, we found that injury to hepatocytes and cells called liver sinusoidal endothelial cells resulted in the induction of hepatocyte elimination by YAP.”

Specifically, the team showed that YAP is activated upon damage to cells in the liver, leading to the migration of these cells to special blood vessels in the liver. There, they undergo apoptotic cell death and are engulfed and degraded by Kupffer cells which are liver-specific immune cells. These findings could also help explain the causes of liver diseases associated with dysregulation of some of the key processes that enable this organ to function.

“This shows how effectively the liver can regulate its own size and function,” said Assistant Professor Norio Miyamura of TMDU who is a co-author of the study. “Without regulatory mechanisms like this, the liver would be much more susceptible to becoming enlarged or developing cancerous growths.”

The article can be found at: Miyamura et al. (2017) YAP Determines the Cell Fate of Injured Mouse Hepatocytes in vivo.


Source: Tokyo Medical and Dental University.
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