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From Quantitative to Qualitative Aspects of Lipids: Toward a Paradigm Shift in the Treatment of Lifestyle-Related Diseases2013.03.31
Lipid and Energy Metabolism
Professor Hitoshi Shimano, Faculty of Medicine
31 (21 faculty members, 1 postdoctoral fellow, 9 from other organizations)
lipids, diabetes, arteriosclerosis, lifestyle-related diseases, transcription factors
Modern society suffers from an epidemic of overeating and underactivity, a rare phenomenon in the long history of human and land creature. Along with a recent trend toward a positive nutrient intake balance, i.e., excessive energy intake, metabolic or lifestyle-related diseases such as diabetes, hyperlipidemia, and obesity, have become a major health issue among human being. From a new perspective, focusing on the quantity and quality of lipids accumulated in the body, the research unit “Lipid and Energy Metabolism” conducts comprehensive studies regarding lifestyle-related diseases from the molecular to whole-organism level (Figure 1).
Toward a comprehensive understanding of lipid metabolism from the molecular to whole-organism level
It is necessary to conduct comprehensive studies across a range of scales from the molecular to whole-organism level to elucidate the pathology of a disease and develop effective treatment strategies against it. We suggest that the unbalanced expression of genes regulating lipid metabolism as well as the accumulation of lipids in the body may be key to understanding the pathology of metabolic disorders. Based on this, and using the most advanced technologies available, we are working on three research projects that integrate animal studies and cell-based experiments aiming to:
1. Characterize, at the gene level, the mechanisms by which the body recognizes a lack or excess of energy (Figure 2)
2. Analyze transcription factors that function during energy excess and depletion (satiation and starvation), and elucidate the regulatory mechanisms of lipid metabolism in the whole body, organs and cells (Figure 2)
3. Clarify the effects of differences in the quality of lipids (especially fatty acid composition) accumulated in different organs on the pathologies of different lifestyle-related diseases to provide a new and comprehensive treatment strategy against these problems (Figure 3).
Quality of tissue lipids: The fatty acid composition is a novel key factor in the development of lifestyle-related diseases
Obesity-related or lifestyle-related diseases are thought to be caused by obesity. Although appropriate adjustment of energy balance and resolution of obesity still remains an important recommendation, but hard to continue, approaches focusing only on the quantity of lipids accumulated in the body would be insufficient to develop effective strategies for the prevention and treatment of lifestyle-related diseases. Switching the focus to quality of lipids, we have conducted extensive studies on Elovl6, an enzyme that modulates the quality (fatty acid composition) of lipids stored in the body, since we identified it. In a study using an obese diabetic mouse model, alterations in the tissue fatty acid composition by genetic modification of this enzyme resulted in increased insulin sensitivity and decreased blood glucose levels, despite there being no marked changes in the amount of lipids in organs, leading to protection against diabetes, arteriosclerosis, and hepatic steatosis (Figure 3, left). This suggests the potential for a novel therapeutic approach to lifestyle-related diseases targeting Elovl6 in which the management of obesity is not necessary.
Furthermore, it is interesting that the tissue fatty acid composition has been shown to play important roles in the brain and lung to influence behavior and respiratory activity, respectively (Figure 3, right). Through research on both quantitative aspects of the regulation of energy metabolism and qualitative aspects of the regulation of tissue lipids, we are continuing our efforts to elucidate the involvement of such regulatory mechanisms in biological phenomena and disease pathologies to develop new treatment strategies against lifestyle-related diseases.
● Development of a novel treatment strategy for obesity-, energy metabolism- and lifestyle-related diseases with a particular focus on the tissue fatty acid composition.
● Nurturing medical and research personnel who are capable of undertaking comprehensive studies on diseases across a range of scales from the molecular to whole-organism level.
(Interviewed on October 10, 2013)