Dynamic atlas of liver proteins may lead to new drug development

Disease and treatment 9. aug 2022 3 min Postdoctoral Fellow Lili Niu Written by Kristian Sjøgren

Researchers have almost completely mapped all the proteins in the various cells of the liver. This proteome atlas can be used for research to advance knowledge about various liver-related diseases and to develop new drugs to combat many diseases originating in the liver.

The liver is one of the most important organs. It plays a major role in metabolism, digestion and synthesising proteins.

The liver has many types of cells that organise at least 10,000 proteins in various signalling pathways that carry out many essential functions.

The proteins in the liver interact with each other and with the rest of the body in a complex yet closely coordinated network, and researchers now understand this much better after creating an atlas of more than 10,000 liver proteins and the associated signalling pathways.

The atlas provides new insight into liver-related disease and provides pathways to develop useful drugs.

“For example, the liver has different types of cells, and each has its own specialised role in maintaining good liver functioning. Targeting specific types of cells is useful in developing new drugs, and our proteome atlas enables drugs to be developed with fewer side-effects by targeting the proteins that are specific to certain types of cells,” explains a researcher behind the study, Lili Niu, a Postdoctoral Fellow from the Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen.

The research, which was led by Matthias Mann, Professor and Head of Research at the Novo Nordisk Foundation Center for Protein Research, has been published in Molecular Systems Biology.

Technology for mapping 10,000 liver proteins

Researchers have previously tried to map all proteins in the liver: the liver proteome.

Until recently, however, they could not map more than 7,000 proteins, which is like looking at an atlas from the 15th century: a lot is missing.

However, the technology for protein mapping has improved, and Lili Niu used very effective methods to extract proteins from samples and to identify more liver proteins using mass spectrometry.

Mass spectrometry measures the ratio of mass to charge of one or more molecules in a sample: in this case, a sample with a mixture of peptides with specific amino acid sequences in the form of proteins.

Optimising each step in the process enabled the liver proteins to be identified and their relative quantities across various types of cells to be determined.

In addition to creating a proteome atlas with more than 10,000 liver proteins, Lili Niu also mapped which proteins are found in each type of liver cells and how the quantity of proteins in the cells changes over time.

“Just analysing one sample with different cells in it and finding some downregulated proteins does not identify where the proteins come from and what type of drug is needed to combat it. With our proteome atlas, we can determine the relative quantity of proteins in each type of cell, which can be used to identify the cellular origin of protein differences in the development of disease,” says Lili Niu.

Liver cells behave differently in the laboratory

Studying the proteome in liver cells over time can also be useful for developing new drugs.

In one of her experiments, Lili Niu investigated how liver cells change their protein expression over time when isolated from a liver sample and cultured in the laboratory.

Liver cells do not usually exist in isolation and are usually in an organ with other cells. This affects their overall protein expression because isolated cells no longer send signals to and receive signals from the natural environment.

The researchers confirmed this in their experiments, and the proteome atlas includes which signalling pathways and processes change over time when liver cells are isolated and which are maintained.

“This knowledge is very important in developing drugs. You must determine how the cells respond to a given drug and then monitor whether the results from the laboratory are also relevant in the liver of a living person in which the cells are involved in complex interactions with others,” explains Lili Niu.

Identifying protein changes associated with liver disease

In the third part of the study, the researchers demonstrated that their aim of using the proteome atlas to advance knowledge on liver disease was not hypothetical.

To that end, the researchers acquired liver tissue samples from 45 people with nonalcoholic fatty liver disease or liver cirrhosis and from several healthy controls.

The researchers made protein profiles for all the liver samples and could identify the liver-related protein changes associated with nonalcoholic fatty liver disease and liver cirrhosis.

“Now we can tell drug developers what proteins and signalling pathways change as these diseases develop. This is valuable knowledge because it will probably be beneficial in targeting treatments for these proteins and signalling pathways,” concludes Lili Niu.

Dynamic human liver proteome atlas reveals functional insights into disease pathways” has been published in Molecular Systems Biology. Several authors are employed by the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

Dynamic human liver proteome atlas reveals functional insights into disease pathways” is published in Molecular Systems Biology. Several of the authors are employed at the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

My reseach interests focus on appling mass-spectrometry based proteomics and proteogenomics to understand human proteome variation in health and disea...

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