In a groundbreaking study published in Science, researchers at the Children's Medical Center Research Institute at UT Southwestern have uncovered a crucial mechanism that helps protect the liver during regeneration. The team, led by Associate Professor Prashant Mishra, M.D., Ph.D., found that liver cells maintain a vital metabolic inflexibility to starve dysfunctional cells and prevent damage from spreading during the regeneration process.
The study focused on hepatocytes, the primary functional cells of the liver. Under normal conditions, these cells rely on their mitochondria to process fatty acids, which serve as a key energy source during regeneration. However, when mitochondria become damaged, hepatocytes activate an enzyme called PDK4. This enzyme acts as a metabolic gatekeeper, restricting cells from shifting to alternative energy sources and ultimately leading to the death of damaged cells.
Dr. Mishra explained the significance of this finding, stating, Although metabolic flexibility has been largely described as beneficial because it gives cells the ability to tolerate shifting environments or alternative nutritional sources, our findings suggest flexibility can also be detrimental by allowing damaged cells to survive. This discovery challenges the conventional wisdom that metabolic flexibility is always advantageous, revealing a nuanced approach employed by the liver to maintain its health during regeneration.
The research team conducted a series of experiments to understand this process better. They first examined healthy liver cells under normal and regenerative conditions, observing that fatty acids from other parts of the body were transported through the blood to fuel liver regeneration. When fatty acid transit was blocked, healthy livers demonstrated flexibility by shifting to other energy sources, such as glucose. However, when the researchers studied livers with mitochondrial gene mutations, they found that damaged cells were unable to use fatty acids during regeneration and did not shift to other energy sources, effectively halting the regeneration process.
To unravel the mechanism behind this inflexibility, the Mishra Lab investigated genes controlling a cell's ability to use alternate energy sources. Their analysis revealed increased levels of the PDK4 gene, which negatively regulates a pathway necessary for generating energy from glucose. When PDK4 was blocked, damaged liver cells regained metabolic flexibility and could use other energy sources to proliferate. This finding highlighted the critical role of PDK4 in maintaining the metabolic inflexibility that prevents damaged cells from spreading during liver regeneration.
The implications of this research extend beyond liver regeneration. Dr. Mishra noted that mitochondrial damage is often observed in common human diseases, including cancer. By identifying the mechanisms cells use to prevent damage from spreading, researchers hope to harness these processes to combat disease and promote health. The study also builds on previous research from the Mishra Lab, which demonstrated the importance of healthy mitochondria in proper liver function and fatty acid metabolism.
This discovery opens up new avenues for understanding and potentially treating liver diseases. The research illustrates how regenerating livers regulate cell proliferation and how disabling the key regulator PDK4 can result in unhealthy livers with fat accumulation and steatosis, commonly known as fatty liver disease. As Dr. Mishra and his team continue to explore these mechanisms, their work may lead to novel therapeutic approaches for a range of liver conditions and other diseases involving mitochondrial dysfunction.
