Lipids, one of the three major nutrients,
In addition to serving as an energy source for living organisms, it also has a variety of other functions.
Recent studies have revealed its connection with many diseases.
The Department of Physical Pharmacology at Teikyo University's Faculty of Pharmaceutical Sciences Pharmaceutical Sciences has been conducting research for many years focusing on the relationship between lipids and disease.
Professor Kazuaki Yokoyama and Associate Professor Kotaro Hama
Discovered the relationship between colon cancer, congenital metabolic disorders, and very long-chain fatty acids.
He has developed his own molecular probes to track the metabolic process of fatty acids.
He continues his research to further deepen his understanding of lipids.
A wide variety of structures and functions
Tens of thousands of types of lipids
Of the nutrients that humans ingest from food, the three major nutrients (energy-producing nutrients) are protein, fat, and carbohydrates (sugars), which are the energy sources for the body. Among these, fats are found in large quantities in oils such as salad oil and olive oil, dairy products, and meat, and are necessary sources of energy, but neutral fats and cholesterol can cause lifestyle-related diseases such as obesity. Because of this, they tend to have a bad image.
On the other hand, lipids also play an important role as materials for cell membranes and intracellular information transmitters. Phospholipids, which are one type of lipid, are the main components of cell membranes and have a water-soluble (hydrophilic) head and a water-insoluble (hydrophobic) tail. These phospholipids form a double structure on the cell surface, with their hydrophobic tails facing each other, thereby blocking the inside and outside of the cell. In addition, lipids called prostaglandins act as neurotransmitters and hormones that transmit information within cells and between cells, and are known as physiologically active substances that cause pain and fever.
Three major functions of lipids
In this way, lipids, which are essential for life activities, are substances made by linking carbon and hydrogen, but depending on how they are linked, they can become a wide variety of lipids with different structures. Based on past biochemical research, it is estimated that there are thousands to tens of thousands of lipids, but some researchers argue that this is only a small portion. Furthermore, differences in structure lead to differences in function and produce various effects within the body.
Associate Professor Kotaro Hama, who is conducting research focusing on the relationship between lipids and disease, explains as follows:
"Lipid research is endless; just when we think we've discovered the role of a new lipid, another lipid is discovered. However, by utilizing the latest mass spectrometers, we can now comprehensively investigate lipid structures, and our understanding of the roles of lipids is deepening."
Inborn errors of metabolism and colorectal cancer
Clarifying the relationship between extremely long chain fatty acids
While there are said to be tens of thousands of types of lipids, Associate Professor Hama and his colleagues are targeting very long-chain fatty acids. Fatty acids, the basic units that make up lipids, have different properties depending on their length, and compared to short-chain fatty acids with 2 to 6 carbon atoms and medium-chain fatty acids with 8 or 10 carbon atoms, very long-chain fatty acids are considerably longer, with 23 or more carbon atoms. Lipids, which are inherently difficult to dissolve in water, become even less soluble when they become this long, and as they accumulate in large quantities in the body, they can cause a variety of diseases.
One of the diseases that is said to be closely related to extremely long chain fatty acids is inborn errors of metabolism. Congenital metabolic disorders, in which people are born with malfunctions in certain enzymes and excessive amounts of amino acids and carbohydrates accumulate in the body, have a variety of symptoms depending on the substances that accumulate, and many are difficult to treat. Among the inborn errors of metabolism, lipid metabolism disorder (adrenoleukodystrophy), in which lipids accumulate, is a disease with symptoms such as adrenal insufficiency, central nervous system degeneration, and developmental delay, and is designated as an intractable disease in Japan. There is.
There are many unknowns about these diseases, including the mechanisms of their onset. Associate Professor Hama discovered that in congenital metabolic disorders, very long-chain fatty acids are regularly bound to some of the phospholipids in the cell membrane.
As a biochemist, I would like to clarify even metabolic processes in order to elucidate the mechanism of pathogenesis. With the advent of mass spectrometry, it is now possible to examine individual lipid molecules from the standpoint of molecular weight. Using this technology, Dr. Hama conducted a thorough investigation and found that very long-chain fatty acids are bound to phospholipids in inborn errors of metabolism," says Kazuaki Yokoyama, Professor.
By unraveling the structure of extremely long-chain fatty acids and their metabolic processes within the body, we are attempting to elucidate the mechanisms of the disease itself and its relationship to symptoms.
Similarly, colorectal cancer is another disease that has been linked to lipids. The number of patients with colorectal cancer is still increasing along with the spread of fatty Western diets, but it is still unclear which lipids are "bad". Hama Associate Professor focused on this part of the disease, and through joint research with the Teikyo University Hospital Surgery Lower Gastrointestinal Group and others, found that very long-chain fatty acids in the form of triglycerides (triacylglycerols), not phospholipids, accumulate in the tumor site of colon cancer.
Rather than directly treating multiple myeloma, Senior Assistant Professor Shirasaki's research focuses on finding keys to improving treatment effectiveness. Using an experimental tool called "CRISPR screening," which he learned while studying in the United States, he analyzes tens of millions of cells to identify genes involved in drug resistance and treatment sensitivity. For example, he can identify which genes are causing resistance in cells treated with anti-cancer drugs, and then administer another drug (combination drug) that targets that gene to prolong the effectiveness of the anti-cancer drug.
Make fatty acids “heavy”
Measured with a mass spectrometer
Conventional testing methods for examining fatty acids required measuring the composition of fatty acids broken down by hydrolysis or enzymatic action. However, to clarify the role of long-chain fatty acids in congenital metabolic disorders and colon cancer, it was necessary to clarify the metabolic process by which fatty acids undergo chemical changes in the body. Therefore, Associate Professor Hama first developed a molecular probe that could detect oxidized lipids and oxidized fatty acids using a mass spectrometer.
"The molecular probe we developed in collaboration with organic chemists is an artificial lipid that is metabolized in place of the target lipid, and by incorporating this artificial lipid into cells or living organisms, we can track the metabolic process," explains Associate Professor. The artificial lipid we are creating is one in which all four protons that bond to specific carbons in oxidized fatty acids have been replaced with heavy hydrogen (stable isotope) (deuterated). By introducing these fatty acids, which are four hydrogen heavier, into cells and measuring them with a mass spectrometer, and detecting only the heavier molecules, we can observe the metabolic process of the target fatty acid.
This molecular probe uses catalysts and reagents containing deuterium atoms that are inexpensive and easy to handle, so it can be easily applied to the analysis of a huge variety of lipids. Taking advantage of this mechanism, we can not only track the metabolic process of lipids, but also use it as a biomarker by discovering lipid accumulation that is specific to certain diseases such as colon cancer. It is said that it will be done.
LC-MS measurement example
Example of measuring biological lipids using a mass spectrometer (LC-MS)
Each orange (or brown) dot represents a different type of lipid. Phospholipids and triacylglycerols can be further separated according to their structure and each lipid can be detected.
Discover unknown fatty acids
Leading to the elucidation of unknown functions
In recent years, research equipment for investigating the reactions of fatty acids has advanced, and great progress has been made in elucidating the enzymes that act on lipids. Next, Associate Professor will focus on the functions of these enzymes, aiming to clarify how each lipid produced by the enzymes is linked to disease.
"For example, we would like to clarify whether VLCs are the direct cause of inborn errors of metabolism (causal relationship), or whether the increase in VLCs is the result of another cause of the disease (correlation). If we can find out, we can use this information as a therapeutic target for drug development, etc." (Associate Professor)
Professor Yokoyama and Associate Professor Hama have been solely focused on lipid research up until now, and so they say that in the future they hope to unravel as many mysteries surrounding lipids as possible.
"Of the four major components of living organisms - nucleic acids, proteins, sugars, and lipids - only lipids are hydrophobic, and lipids are produced from enzymes, which are proteins, and are not directly encoded by genes. Lipids are interesting because they are a bit unusual, and their relationship to various diseases is now becoming clear. I believe this is important research for the future of medicine," says Professor Yokoyama.
"Lipids are substances whose structure is closely linked to their function, and I really like the clear logic behind the idea that elucidating the mechanisms that determine their structure can directly lead to an understanding of their function. I hope to continue this fascinating research into lipids, and one day discover a new lipid myself." (Associate Professor)
Lipids have played an important role in the birth of life, as it is said that the origin of life lies in the membranes that surround cells. Research is progressing with the passion of researchers who are fascinated by lipids to ``unravel the mysteries of lipids'' and the desire to ``contribute to medicine by clarifying the relationship between lipids and disease.''
