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이명식 (연세대학교 의과대학 의생명과학부)
Prof. Myung-Shik Lee is the first research who demonstrated the role of autophagy in metabolic diseases. Autophagy is a critical intracellular process of turnover and rejuvenation of organelles and proteins. However, nobody had studied the role of autophagy in body metabolism or metabolic disorders such as type 2 diabetes (T2D) until he published the first paper using beta-cell-specific autophagy-knockout mice. In the following studies using mice with autophagy knockout in insulin target tissues such as skeletal muscle, he found the existence of 'mitokine', a cellular hormone release in response to mitochondrial stress. Thus, he elucidated the identity of the first mammalian mitokine (FGF21) and also characterized the mechanism of the mitokine response. Since metabolic effects of dysregulated autophagy were variable depending on the location and severity of autophagy deficiency, he studied the effect of global autophagy insufficiency rather that tissue-specific knockout, and showed that systemic autophagy insufficiency hampers adaptation to metabolic stress and could be a factor in the development of diabetes (Nat Commun 5:4934, 2014). Based on those in vivo results, Prof. Lee conceived a converse experiment. Thus, he identified several autophagy enhancer small molecules employing a luciferase-based screening system of autophagic activity, and one of them was shown to have therapeutic effects against diabetes and metabolic syndrome. In addition to T2D, Prof. Lee has also been studying the pathogenesis of autoimmune type 1 diabetes (T1D). Particularly, he has been interested in the initial event of T1D. It was a long-sought question among immunologists. He found that apoptotic cells undergo secondary necrosis if not removed in time, and that secondary necrotic beta-cells could induce inflammation in macrophages through an innate immune receptor called toll-like receptor 2 (TLR2).
Representative papers
1. Lim H, Lim Y-M, Kim KH, Jeon YE, Park K, Kim J, Hwang HY, Lee DJ, Pagire H, Kwon HJ, Ahn JH, Lee M-S. A novel autophagy enhancer as a therapeutic agent against metabolic syndrome and diabetes. Nat Commun 9:1438, 2018
2. Kim KH, Lee M-S. Autophagy- a key player in cellular and body metabolism. Nature Rev Endocrinol 10: 322-337, 2014
3. Kim KH, Jeong YT, Oh H, Kim S-H, Cho JM, Kim Y-N, Kim SS, Kim D-H, Hur KY, Kim HK, Koh T, Han J, Kim H, Kim J, Back SH, Komatsu M, Chen H, Chan DC, Konishi M, Itoh N, Choi CS, Lee M-S. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing FGF21, a 'mitokine'. Nature Medicine 19:83-92, 2013
4. Kim HS, Han MS, Chung KW, Kim S, Kim E, Kim MJ, Jang E, Lee HA, Youn J, Akira S, Lee M-S. Toll-like receptor 2 senses β-cell death and contributes to the initiation of autoimmune diabetes. Immunity 27:321-333, 2007
5. Jung H-S, Chung KW, Kim JW, Kim J, Komatsu M, Tanaka K, Nguyen YH, Kang TM, Yoon K-H, Kim J-W, Jeong YT, Han MS, Lee M-K, Kim K-W, Shin J, Lee M-S. Loss of Autophagy Diminishes Pancreatic β-Cell Mass and Function with Resultant Hyperglycemia. Cell Metab 8:318-324, 2008
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