
Unlocking the Secrets of Liver Cells
Liver cells may look identical under the microscope, but they perform vastly different tasks. Understanding this phenomenon drives the research of Nicolaj Ibsgaard Toft, who recently completed his Ph.D. on the activity of liver cells.
Liver cells are not identical – a fact that researchers have increasingly understood since 10–15 years ago when it became possible to study individual cells and identify which genes are active in each liver cell.
Under the microscope, liver cells look completely identical. However, they perform widely different functions in the liver.
- When you look at liver cells under a microscope, you truly can’t see any differences between them. Yet, two cells that look identical and are located right next to each other in the liver can have entirely different functions. That fascinates me, says Nicolaj Ibsgaard Toft, who chose to focus his Ph.D. research on the activity of liver cells – more precisely called hepatocytes.
”All the liver diseases I can think of affect different areas of the liver lobules, so there's a real need to better understand this vital organ.
The liver serves several metabolic functions, including breaking down waste and toxins (e.g., alcohol) and helping the body utilize nutrients from food. The liver in an adult human weighs about 1.5 kg and is supplied with blood vessels that act as conveyor belts, branching through the liver to deliver substances like waste that need to be removed.
The liver consists of numerous small, hexagonal shaped column-like structures called lobules, about 1 mm in diameter. Blood enters the corners of these lobules and flows toward the center through small blood vessels. In the middle of the lobules is a vein through which blood exits.
When you think of the liver as a factory with worker cells that have different tasks along the assembly line, it makes sense that each hepatocyte has specific duties. The big question is: How do individual hepatocytes know what their specific task is?
- We know that proteins regulate these activities. More specifically, it’s transcription factors that control which genes are active in each hepatocyte, explains Nicolaj Ibsgaard Toft.
- It’s important to map these processes in a healthy liver. Understanding how a healthy liver works helps us better understand a diseased liver and thereby start developing better treatments for liver diseases.
Normal processes stopped
In his Ph.D. project, Nicolaj Ibsgaard Toft focused on one particular transcription factor and tested its role in mice. First, he removed the transcription factor in mice and observed that certain hepatocyte processes became active in areas of the lobules where they normally wouldn’t occur.
- You can imagine that there are three zones in the liver lobules: the outer zone where blood enters, the middle zone, and the inner zone. What we saw was that processes that normally only occur in the outer zone also began happening in the inner zone after we removed the transcription factor.
To further test this, Nicolaj Ibsgaard Toft also tried the opposite – overexpressing the transcription factor to see if the reverse would happen. It did: the processes that normally occur in the outer zone stopped.
- In essence, we identified the transcription factor that controls where this specific process occurs.
Getting rid of ammonia
The process in question is the metabolism of ammonia, which is released when proteins and amino acids are broken down - especially when we consume protein-rich food or fast long enough that the body starts breaking down muscles.
Ammonia is toxic to the body and must be transported via the blood to the liver for conversion. In the liver, ammonia is converted into urea, allowing the body to safely excrete it.
In a healthy liver, this conversion of ammonia primarily takes place in the outer zone, while the inner zone serves as a buffer to handle excess ammonia.
- That’s the process we were able to control by removing or overexpressing our transcription factor: whether – and where – the liver would convert ammonia to urea, Nicolaj explains.
The transcription factor studied in Nicolaj’s Ph.D. research is just one of many that make the liver function. There are many transcription factors – and many potential points of failure that can lead to disease.
- There are many different liver diseases. All the liver diseases I can think of affect different areas of the liver lobules, so there’s a real need to better understand this vital organ” he says.
He is continuing his research on hepatocytes as a postdoc in Lars Grøntved’s research group at the Department of Biochemistry and Molecular Biology. Grøntved’s group is one of nine research groups within the Functional Genomics & Metabolism Research Unit at the department.
Meet the researcher
Nicolaj Ibsgaard Toft wrote his P.D thesis, Spatial and Temporal Regulation of the Hepatic Chromatin Landscape, under the supervision of Associate Professor Lars Grøntved. Today, he works as a postdoc in Lars Grøntved's research group at the Department of Biochemistry and Molecular Biology.