代謝医学分野 酒井寿郎 教授、第43回 日本動脈硬化学会 （2011年7月16日開催） 第6回 五島雄一郎 賞 を受賞
2011年07月19日 00時00分00秒 (#27)
酒井寿郎 日本動脈硬化学会 第6回 五島雄一郎賞（平成22年度）
代謝医学分野 酒井寿郎 教授、第43回 日本動脈硬化学会 （２０１１年７月1６日開催）
第6回 五島雄一郎 賞 を受賞いたしました。
Atherosclerosis - Genetics to Epi-genomics
Division of Metabolic Medicine, RCAST,
The University of Tokyo
For more than a century, genetics has been a powerful tool to discover the causes of disease and their molecular basis. The discovery of the LDL receptor by Drs Goldstein & Brown, for example, enabled dramatic progress towards the elucidation of the mechanisms that mediate cholesterol homeostasis. This work showed that one of the most common genetic diseases in humans, familiar hypercholesterolemia, results from genetic defects of the LDL receptor. Expression of the LDL receptor gene is tightly regulated by cholesterol levels. This ensures that cells avoid the twin pitfalls of over accumulation of cholesterol on the one hand, and of insufficient cholesterol on the other. Transcriptional regulation of the LDL receptor gene is largely the work of SREBP. SREBP is a membrane-bound transcription factor that resides as an inactive form in the endoplasmic reticulum (ER). In order for SREBP to become transcriptionally-active, its amino-terminal portion must be cleaved from the membrane. Using somatic cell genetics, together with expression cloning techniques, my colleagues and I in the Brown and Goldstein lab discovered the two-step proteolytic activation of SREBP and identified the two distinct proteases involved.
It is now well known that both genetic factors and environmental factors are important in developing metabolic disorders such as obesity, type 2 diabetes, and atherosclerosis. Environmental factors can alter the way our genes are expressed through the mechanism of epigenetic changes. I sought to understand the role of epigenetic alteration of metabolic gene expression in order to test my hypothesis that the metabolic syndrome and cardiovascular disease can be caused at least in part by altered "histone modifications," which affect DNA.
Based on this hypothesis, my colleagues in my laboratory and I searched genes for chromatin modifications that may account for their altered expression and, thus, for obesity and metabolic disorders. PPARγ is a master regulator of adipogenesis and its agonist is an insulin-sensitizer. We hypothesized that PPARγ, regulates epigenetic changes to the genome. Such epigenomic changes are pivotal in cell differentiation. We used chromatin immunoprecipitation sequencing (ChIP-seq) analysis in 3T3L1 adipocytes to reveal that PPARγ binds to several genes that encode histone lysine methyltransferases. These include H3K9 methyl transferase and H4K20 mono-methyl transferase. Remarkably, mice deficient in H3K9 demethylase activity (JMJD1a-/- mice) exhibit adult onset obesity and insulin resistance. This result confirms my hypothesis.
I will present an overview of my studies of lipid and glucose homeostasis, energy expenditure, metabolic disorders and atherosclerosis starting from somatic cell genetics and moving on to epigeomics in animal models.