• #019 Professor Hitoshi Shimano, Faculty of Medicine

    03 10, 2014

    New Research Area Revealed by Knockout Mice and the Growing Circle of Collaborative Research

    Tsukuba Future #019

    Prof. Shimano, head of the Department of Metabolism and Endocrinology at the University of Tsukuba Hospital, reached a significant turning point 20 years ago when studying in the United States. To research blood-borne lipid metabolism, Prof. Shimano went to the mecca of cholesterol metabolism research—the lab of Nobel Prize recipients Joseph L. Goldstein and Michael S. Brown at the University of Texas Southwestern Medical Center. Prof. Shimano's research topic was the functioning of cholesterol-lowering statins, not in test tubes or cell cultures but actually in living subjects. Sterol Regulatory Element-Binding Proteins (SREBPs) had only recently been discovered. Further investigation revealed two types—SREBP-1 and SREBP-2. The latter is related to cholesterol metabolism, while the former, discovered through research on mice, is related separately to lipid metabolism—fatty acid and triglyceride present in high amounts in fat. The over-expression of SREBP-1 in the liver results in a fatty liver. The above-mentioned Nobel recipients, however, had no time to take an interest in this area, as they were determined to stay focused on cholesterol metabolism. Their policy was to not overextend the scope of their research as time was limited and it could dilute the research. Given that policy, Prof. Shimano decided to focus his research on fatty acid metabolism.

    It is difficult to get Prof. Shimano to stop talking about research once he gets going.

    While studying lipid metabolism in the blood and internal organs, Prof. Shimano discovered an interesting phenomenon. The SREBP-1 proteins are like orchestra conductors. They issue the commands in a normal state for the sugar and carbohydrates absorbed through food intake to be converted and stored in the body as fat. However, once food is withheld until a state of hunger is experienced and then food is ingested, overeating will take place and the "go sign" for the synthesis of fat stays lit without turning off. The more one eats, the more the absorbed sugar, carbohydrates, and lipids are stored in the body as fat. This kind of accumulation of fat can lead to lifestyle diseases. Prof. Shimano also learned that not all stored fat does bad things. As proof, some people are overweight but healthy. The quality of the accumulated fat is the problem. In the process of researching this, Prof. Shimano's research team discovered Elovl6, an enzyme that regulates the "quality" of the fatty acids that make up fat. Fatty acids are made up of three types of atoms—carbon, hydrogen, and oxygen. The type of fatty acid is determined by the carbon count in the chain. Elovl6 is involved in the synthesis of fatty acids with a chain of 18 carbons or more. One well-known yardstick for types of fatty acids was the "thickness" of the chain. The effects that polyunsaturated fatty acids (fish oil) and saturated fatty acids (meat fat) have upon health and illness were also widely known, but the length of the chain was a new area that points to lipid quality.

    The action of the Elovl6 enzyme is related to the functioning and disorders of many organs such as the brain, lungs, and liver.

    Fats (lipids) are also involved in metabolism, obesity, hardening of the arteries, and other chronic conditions, as well as localized inflammation. Prof. Shimano extended the focus of research to the physiological significance of lipid synthesis pathways and their involvement in the condition of lifestyle diseases. He used animal models to demonstrate the mechanisms and at the same time set the goal of working to elucidate the mechanisms at the cellular level. In particular he has created knockout mice in which the gene for the Elovl6 enzyme, which controls the quality of fatty acids, is inactive, and is using those mice to carry out his research.

    The mice without this "knocked out" Elovl6 enzyme would become overweight and develop a fatty liver, but would not develop diabetes. This indicates a low occurrence of lifestyle diseases. To put it another way, by obstructing the action of this enzyme, new methods of treatment may be discovered for improving insulin resistance and treating diabetes and cardiovascular risks in an ongoing state of obesity. Also, the loss of this enzyme functioning causes various noteworthy abnormalities to appear in different parts of the body. For example, if the enzyme does not function in the brain, the brain grows in size and preferences and behavior also change. Exploration decreases and a propensity toward anxiety disorder arises. In other words, the quality of fat affects the structure of the brain and its functioning. It also became clear that suppression of the enzyme's action in the lungs contributes to lung disorders. The cell membranes in the body are made up of lipids. The metabolism of lipids therefore affects all different parts of the body and is related not only to nutrition and metabolism but to various biological phenomena—inflammation, brain function, and growth. Prof. Shimano and his research team are creating mice in which the enzyme does not function for specific organs to study each relationship in greater depth. Naturally, not all of this work can be accomplished in his own research lab, so Prof. Shimano joins up with researchers both inside and outside the university in various fields to extend the circle of this research. Of course he is also working to train young doctors in the Department of Metabolism and Endocrinology who are interested in research and educational activities on preventing diabetes through medical treatment.

    Students of different backgrounds, not only in medicine, conduct research at Prof. Shimano's lab. This diversity expands the scope of research.

    Prof. Shimano's research, which was initially aimed at a highly focused target, keeps expanding. Rather than adhere strictly to boundaries imposed by existing fields of specialization, Prof. Shimano has set his sights on the joy of discovering new truths by searching in-depth for phenomena based on pure intellectual curiosity. At the same time, he holds stock in the value of a multi-faceted approach to contribute to discoveries in previously unimagined ways. There is a limit to what one person can accomplish alone. But when many people join hands, the possibilities grow exponentially. That is Prof. Shimano's policy.

    Article by Science Communicator at the Office of Public Relations

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