Research Interests
[Nuclear receptor, Metabolic Syndrome: obesity, diabetes, fatty liver; colon and hepatoma cancer]
Dr. Wang, Ph.D., received her postdoctoral training in the Department of Molecular and Cellular Biology at Baylor College of Medicine. She began as Assistant Professor of Medicine with adjunct appointment in Pharmacology and Toxicology at KUMC in October 2004. Her overall research focus is on the central role of the orphan nuclear receptor SHP (small-heterodimer partner) in metabolic diseases.
The metabolic syndrome is a cluster of interrelated common clinical disorders, including obesity, insulin resistance, glucose intolerance, hypertension and dyslipidemia. Studies of global SHP null mice revealed that SHP is involved in several of the primary aspects of the metabolic syndrome. When subjected to appropriate stresses, SHP null mice exhibited a number of intriguing phenotypes including loss of negative feedback regulation of bile-acid synthesis (Dev Cell, 02), resistance to cholesterol and bile-acid induced liver damage (JBC, 03), and loss of inhibitory effects of bile acids on hepatic triglyceride production (JCI, 04). In addition, under the challenge of a high fat diet, SHP null mice were resistant to diet induced obesity and diabetes (Cell Metab, 05). Moreover, the loss of SHP in SHP null mice resulted in a dramatic increase in islet insulin secretion and peripheral insulin sensitivity (Mol Endocrinol, 06). Furthermore, OB/SHP double null mice were protected against fatty liver (steatosis), and had marked increases in glucose tolerance and insulin sensitivity, as well as in islet insulin secretion (Hepatology, 06). Dr. Wang’s recent finding demonstrates that SHP regulates cell cycle progression and tumorigenesis, thus may function as a novel tumor suppressor (under review, 06).
The above findings suggest important regulatory roles of SHP in obesity, diabetes, fatty liver and cancer. Thus, this forms an integrated research program aimed at understanding the molecular basis of how SHP regulates these important public health problems. The current major on-going research projects in Dr. Wang’s laboratory are:
1. To understand the regulatory functions of SHP in pancreatic islet insulin secretion and in liver insulin sensitivity, and to determine the cellular and molecular mechanisms by which SHP regulates the development of type 2 diabetes.
2. To investigate the regulatory functions of SHP in lipid metabolic and inflammatory pathways involved in non-alcoholic fatty liver disease (NAFLD), and to understand the molecular basis of how SHP deficiency prevents NAFLD in mice with diabetes and obesity.
3. To determine the molecular mechanisms by which SHP regulates colon and hepatic carcinogenesis.
Major publications
Wang L et al., Proc Natl Acad Sci USA98, 361-366 (2001)
Wang L et al., Developmental Cell2, 721-731 (2002)
Wang L et al., J Biol Chem278, 44475-44481 (2003)
Watanabe M, Houton SM, Wang L et al., J Clin Invest113, 1408-1418 (2004)
Wang L et al., Cell Metabolism 2, 227-238 (2005)
Wang L* et al., Mol Endocrinol20, 2671-2681 (2006)
Huang et al., and Wang L*, Hepatology (accepted) (2006)
Selected publications
Park HJ, Lee J, Wang L, Park JH, Kwon HB, Arimura A and Chun SY (2000) Stage-specific statement of pituitary adenylate cyclase activating polypeptide type I receptor messenger ribonucleic acid during ovarian follicle development in the rat. Endocrinology141, 702-709
Park JI, Kim WJ, Wang L, Park HJ, Lee J, Park JH, Kwon HB and Chun SY (2000) Involvement of progesterone in gonadotrophin-induced pituitary adenylate cyclase activating polypeptide gene statement in preovulatory follicles of rat ovary. Mol Human Reprod 6, 238-245
Wang L, Bogerd J, Choi HS, Seong HY, Soh JM, Chun SY, Blomenrohr M, Troskie BE, Millar RP, Yu WH, McCann SM and Kwon HB (2001) Three distinct types of GnRH receptor characterized in the bullfrog. Proc Natl Acad Sci USA98, 361-366
Wang L, Oh DY, Bogerd J, Choi HS, Ahn RS, Seong JY and Kwon HB (2001) Inhibitory activity of alternative splice variants of the bullfrog GnRH receptor-3 on wild type receptor signaling. Endocrinology 142 (9), 4015-4025
Wang L, Yoo MS, Kang HM, Im, WB, Choi HS, Bogerd J and Kwon HB (2001) Cloning and characterization of cDNAs encoding the GnRH1 and GnRH2 precursors from bullfrog (Rana catesbeiana). J Exp Zool 289, 190-201
Wang L, Lee YK, Bundman D, Han YQ, Thevananther S, Kim CS, Chua SS, Wei P, Heyman RA, Karin M and Moore DD (2002) Redundant pathways for negative feedback regulation of bile acid production Dev Cell 2, 721-731
Wang L, Han YQ, Kim CS, Lee YK and Moore DD (2003) Resistance of SHP-null mice to bile acid induced liver damage J Biol Chem278, 44475-44481
Oh da Y, Wang L, Ahn, RS, Park JY, Seong JY and Kwon HB (2003) Differential G protein coupling preference of mammalian and non-mammalian gonadotropin-releasing hormone receptors. Mol Cell Endocrinol 205, 89-98
Seong JY, Wang L, Oh da Y, Yun O, Maiti K, Li JH, Soh JM, Choi HS, Kim KJ, Vaudry H and Kwon HB (2003) Ala/Thr 201 in extracellularloop 2 and Leu/Phe 290 in transmembrane doamin 6 of type-1 frog gonadotropin-releasing hormone receptor confer differential ligand selectivity and signal transduction Endocrinology 144, 454-466
Watanabe M, Houton SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA, Moore DD and Auwerx J (2004) Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest113, 1408-1418
Wang L, Sanyal S, Kim JY, Ju JW, Im WB, Kwon HB and Choi HS (2004) Molecular Cloning and characterization of an amphibian progesterone receptor from Rana dybowskii. Gen Comp Endocrinol 135, 142-149
Wang L, Liu J, Saha P, Huang JS, Chan L, Spiegelman B and Moore DD (2005) The orphan nuclear receptor SHP regulates PGC-1α expression and energy production in brown adipocytes. Cell Metab 2, 227-238 (featured article)
Datta S, Wang L, Moore DD and Osborne TF (2006) Regulation of HMG CoA reductase promoter by nuclear receptors LRH-1 and SHP provide a mechanism for differential regulation of cholesterol synthesis and uptake. J Biol Chem 281, 807-812. Epub 2005 Nov 9
Wang L*, Huang JS, Saha P, Kulkarni RN, Hu M, Kim YD, Park KG, Chan L, Rajan SA, Lee Ik and Moore DD (2006) Nuclear receptor SHP is an important mediator of glucose homeostasis. Mol Endocrinol 20, 2671-2681. Epub 2006 June 27 (*correspondence)
Matsukuma KE, Bennett M, Huang JS, Wang L, Gil G and Osborne TF (2006) Coordinated Control of bile acids and lipogenesis through FXR dependent regulation of fatty acid synthase. J Lipid Res 47, 2754-61. Epub 2006 Sept 6
Soe JH, Huang JS, Park YY, Seong HA, Kim DW, Shong M, Ha HJ, Lee IK, Lee KS, Wang L and Choi HS (2006) Orphan nuclear receptor SHP inhibits TGF-β signaling by repressing smad 3 transactivation. J Biol Chem (accepted) Epub 2006 Oct 30
Farhana L, Dawson M, Leid M, Wang L, Moore DD and Fontana JA (2006) Novel adamantly retinoid analogs bind to small heterodimer partner SHP and modulate the components and activity of the Sin3A complex. Cancer Res (accepted)
Park KG, Lee KM, Seo HY, Suh JH, Kim S, Wang L, Won KC, Lee HW, Park JY, Lee KU, Kim BW, Choi HS and Lee IK (2006) Glucotoxicity in rat insulinoma cell line INS-1 cells is mediated by orphan nuclear receptor SHP. Diabetes (accepted)
Huang JS, Iqbal J, Saha P, Liu J, Chan L, Hussain M, Moore DD and Wang L* (2006) Molecular characterization of the role of orphan receptor SHP in development of fatty liver. Hepatology (accepted) (*correspondence)
Wang L*, Park KT, Kim YH and Moore DD (2006) Dual role of orphan receptor SHP in regulating cellular senescence and transformation. (under review) (*correspondence)
Current lab members:
Jiansheng Huang, Post-doc fellow
Nan He, Post-doc fellow
Richard (Guisheng) Song, Post-doc fellow
Tom (Ningyi) Xu, Post-doc fellow
KyungTae Park, Graduate student
Robert Nedved, Research technician
Yuxia Zhang, Post-doc fellow
Current grant support:
Kansas Masonic Cancer Research Institute (KMCRI)
NIH P20 RR016475 (INBRE program)
NIH 1P20 RR021940 (COBRE program)
American Liver Foundation/American Association for the Study of Liver Diseases (ALF/AASLD)
American Heart Association (AHA)
American Diabetes Association (ADA)
E-mail: lwang2@kumc.edu
Updated 08/29/2006
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The University of Kansas Medical Center