Scientists
Hui-Yu Liu, M.D., Ph.D.
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Education
M.D., University of South China School of Medicine, Hengyang, Hunan, China, 1984.
Ph. D., Biochemistry, Gunma University, Maebashi, Gunma, Japan, 1999.
CIHR Fellow, Cell Biology, Robarts Research Institute, London, Ontario, Canada, 2000-2005.
Research
Insulin is a central regulator of metabolism for glucose, fat and proteins. Insulin predominantly promotes the anabolic, while inhibiting the catabolic processing of all nutrients. In addition, insulin suppresses energy consumption, primarily via the suppression of mitochondrial biogenesis and function. Thus, insulin is an efficient energy-saver, which is necessary in situations in which there is a shortage of food. However, over-exposure to insulin, either because of excessive levels or prolonged duration, can be problematic. For example, insulin resistance, the state of hyperinsulinemia in the setting of normal blood glucose or hyperglycemia, is associated with a variety of metabolic disorders and related diseases, like obesity, diabetes mellitus, cardiovascular diseases, and aging. Consequently, understanding the development of insulin resistance could help in the promotion of improved general health.
My research focuses on insulin signaling. We have approached the study of insulin resistance from several different angles: 1) Searching to identify causative factors behind the development of insulin resistance; through studies on free fatty acids, high glucose and high/long-term insulin exposure, we have found that insulin is the most important determinant for the development of insulin resistance. 2) Demonstrating that insulin continues to function in the setting of insulin resistance. In obese individuals, hyperinsulinemia always is accompanied by hyperlipidemia, indicating an elevated level of lipogenesis. Importantly, we recently found that basal insulin signaling remains high in high-fat diet-fed C57BL/6j mice with insulin resistance and hyperinsulinemia. A higher dose of insulin can maintain euglycemia in diabetic NOD mice with insulin resistance. These observations indicate that insulin continues to work in the setting of insulin resistance, even though these animals are less responsive to acute insulin treatment. 3) Treating diabetes with reagents that bypass insulin signaling: individuals with insulin resistance are resistant to acute insulin treatment, as insulin signaling is blunted. This line of defence can be overcome by using larger amounts of insulin; however, this approach may exacerbate insulin resistance. We have made efforts to develop replacements that bypass insulin signaling to manipulate diabetes. We have discovered that neutrophil-derived α-defensins (HNP-1 and HNP-2) and certain stromal cell-derived factors (SDF-1α and -1β) can inhibit hepatic glucose production in a Src-Akt-dependent signaling pathway that is distinct to insulin.
Our understanding of the mechanisms behind the development of insulin resistance is the key to develop novel therapeutic avenues, by which to manipulate both obesity and diabetes. Additional efforts will be made to detect existing small endogenous molecules that can inhibit glucose production and simultaneously reduce lipogenesis. Our research will involve the use of multiple techniques in biochemistry, molecular cloning, cell biology, proteomics and physiology, which should provide numerous opportunities for trainees who need to acquire technical expertise in a multi-disciplinary environment.
Selected Publications
Liu HY and Meakin SO. (2002) ShcB and ShcC activation by the Trk family of receptor tyrosine kinases. Journal of Biological Chemistry 277: 26046-26056.
Liu HY, MacDonad JIS, Li C, and Meakin SO. (2005) Human Tid1 associates with the Trk family of receptor tyrosine kinases and facilitates neurite outgrowth in nnr5-TrkA cells. Journal of Biological Chemistry 280(20): 19461-19471.
Liu HY, Collins QF, Xiong Y, Moukdar F, Lupo EG, Liu Z, and Cao W. (2007) Prolonged treatment of primary hepatocytes with oleate induces insulin resistance through p38 mitogen-activated protein kinase. Journal of Biological Chemistry 282(19): 14205-14212.
Syeda F*, Liu HY*, Tullis E, Liu M, Slutsky AS, and Zhang H. (2008) Differential signaling mechanisms of HNP-induced IL-8 production in human lung epithelial cells and monocytes. Journal of Cell Physiology 214(3): 820-827.
Liu HY, Collins QF, Moukdar F, Zhuo D, Han J, Hong T, Collins S and Cao W. (2008) Suppression of hepatic glucose production by human neutrophil alpha-defensins through a signaling pathway distinct from insulin. Journal of Biological Chemistry 283(18): 12056-12063.
Liu HY*, Wen GB, Han J, Hong T, Zhuo D, Liu Z, and Cao W*. (2008) Inhibition of hepatic gluconeogenesis in primary hepatocytes by stromal cell-derived factor-1 (SDF-1) through a c-Src/Akt-dependent signaling pathway. Journal of Biological Chemistry 283 (45): 30642-30649.
Liu HY, Yehuda-Shnaidman E, Hong T, Han J, Liu Z, Pi J, and Cao W. (2009) Prolonged exposure to insulin suppresses mitochondrial production in primary hepatocytes. Journal of Biological Chemistry 284(21): 14087-14095.
Liu HY*, Hong T*, Wen GB, Han J, Zhuo D, Liu Z, and Cao W. (2009) Increased basal level of Akt-dependent insulin signaling may be responsible for the development of insulin resistance. Am J Physiol Endocrinol Metab 297: E898-E906.
Liu HY, Cao SY, Hong T, Han J, Liu Z, and Cao W. (2009) Insulin is a stronger inducer of insulin resistance than hyperglycemia in mice with type 1 diabetes mellitus (T1DM). Journal of Biological Chemistry 284 (40): 27090-27100.
Liu HY*, Han J*, Cao SY, Hong T, Zhuo D, Shi J, Liu Z, and Cao W. (2009) Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin. Journal of Biological Chemistry 284 (45): 31484-31492.