Dr. Lee's laboratory mainly focuses on two transcription factors, XBP1 and CREBH, which are involved in endoplasminc reticulum stress response and triglyceride metabolim.
XBP1 is a key regulator of the unfolded protein response (UPR), which is involved in a wide range of physiological and pathological processes. XBP1 is activated during the development of highly secretory cells by its upstream enzyme, I RE1. XBP1 induces a variety of genes involved in protein secretory pathway such ER chaperones, and it promotes ER expansion. Consistent with these molecular functions of XBP1, ablation of XBP1 in mice severely impairs the development of professional secretory cells such plasma B cells and pancreatic acinar cells. His lab aims to further investigate the regulatory mechanism leading to XBP1 activation, and the physical and functional interaction of XBP1 with other factors governing the cellular secretory function.
Interestingly, he found that the mutant mice lacking XBP1 in the liver exhibit drastically low plasma triglyceride and cholesterol levels without fat accumulation in the liver, indicating that XBP1 plays a crucial role in hepatic lipogenesis. This novel function of XBP1 appears to be unrelated to its role in ER expansion and protein secretion, as XBP1 deficient hepatocytes does not exhibit morphological signs of ER dysfunction, defects in apoB100 secretion, increased apoptosis, or activation of XBP1 independent stress markers. Instead, they found that the expression of key lipogenic enzyme genes was reduced in XBP1 deficient liver, implicating that XBP1 directly and indirectly controls the induction of critical genes involved in fatty acid and sterol biosyn thesis. Remarkably, IRE1a specifically cleaved mRNAs of several important genes regulating lipogenesis and lipoprotein metabolism. Thus, the decrease of plasma lipids in XBP1 deficient mice involves two distinct mechanisms; direct transcriptional regulation of lipogenic genes by XBP1, and the degradation of mRNAs by hyper-activation of IRE1a.
Dysregulation of lipid metabolism increasing plasma cholesterol and triglyceride levels is closely associated with coronary artery disease (CAD), obesity and type 2 diabetes. Identifying novel proteins participating in lipid metabolism, which may lead to a clinical improvement in prognosis and effective therapies for human dyslipidemia and CAD is a high priority. A long-term goal of Dr. Lee's research is to understand the molecular mechanism by which IRE1 and XBP1 control lipid metabolism in concert with other metabolic regulators, which might uncover a novel strategy to treat dyslipidemias.
CREB-H belongs to a group of ER transmembrane transcription factors that include SREBPs and ATF6, which are synthesized as precursor forms anchored to the ER membrane. To be transported to the nucleus to carry out their function as transcription factors, they have to be cleaved by site 1 (S1P) and site 2 (S2P) proteases in Golgi apparatus. It has been shown that ER stress and low sterol levels activate ATF6 and SREBPs, respectively, by promoting their translocation to t he Golgi apparatus. CREB-H is also activated by a sequential cleavage by S1P and S2P, but the signal that triggers the mobilization of CREB-H to Golgi is unknown. CREB-H is highly and selectively expressed only in the liver and the small intestine. He recently demonstrated that CREB-H induces the apolipoproteins that are crucial for LPL-mediated TG clearance, and CREBH deficient mice have marked hypertriglyceridemia, secondary to a defect in TG clearance
In the next few years, Dr. Lee will focus on the molecular mechanisms of CREBH in the regulation of triglyceride metabolism. We will also investigate the functional relationship between CREB-H and other important transcription factors and coactivators regulating lipid metabolism, such as SREBPs and PPARs. He will also examine the role of CREB-H in dietary and genetic models of metabolic diseases, such as steatosis, dyslipidemia and atherosclerosis. These studies should define novel signaling pathways that may lead to the discovery of potential targets for developing novel therapeutics for lipid metabolism disorders.