Graduate Center for Nutritional Sciences

Jun Liu, M.D.
Assistant Professor
Department of Pediatrics

B367 BBSRB
Department of Pediatrics
741 South Limestone Street,
Lexington, KY 40536
Tel: 859-257-4055
Fax: 859-257-
email: jliuc@email.uky.edu

Academic Appointments:

• Department of Pediatrics, College of Medicine
• Graduate Center for Nutritional Sciences
• Department of Molecular and Cellular Biochemistry, College of Medicine

Education:

• B.M., Clinical Medicine, Fudan University, Shanghai, China.
• Ph.D., Microbiology, University of Virginia
• Postdoctoral Research Fellow, Internal Medicine, University of Michigan

Awards:

Molecular Medicine Graduate Fellowship, University of Virginia
Life Sciences Institute Postdoctoral Fellowship, University of Michigan
American Diabetes Association Junior Faculty Award
Wethington Award for Excellence in Research

Specific Interest in Nutrition:

Hormonal regulation of energy metabolism in the context of obesity and diabetes

Research:

Obesity has been implicated to predispose a set of illnesses, such as insulin resistance, hypertension, dyslipidemia and hyperglycemia, in the so called metabolic syndrome.  Metabolic syndrome is a strong, independent contributor to the onset of coronary heart disease and type 2 diabetes. Obesity occurs when energy input exceeds energy expenditure, resulting in expanded adipose tissue mass often accompanied by the dysfunction of lipid metabolism.  Our laboratory is pursuing two major areas of research that are relevant to these issues.First, we are interested in studying the molecular mechanisms governing the balance between lipid storage and breakdown in adipose tissue.  In the cases of caloric surplus, adipocytes serve as a fuel depot by synthesizing triglycerides from fatty acids and glucose for storage in lipid droplets.  During starvation and extended exercise, β-adrenergic hormones signal the lipolytic process in which triglycerides are hydrolyzed into fatty acids and glycerol.  Subsequently, free fatty acids and glycerol are released into circulation to supply energy to other tissues and organs.  In human obesity, elevated adipose lipolysis is associated with the development of lipotoxicity in peripheral tissues such as liver and skeletal muscle. The prevalence of lipotoxicity as a pathogenic mechanism in insulin resistance and type 2 diabetes has sharpened the research focus on lipolysis.

In 2004, three groups independently discovered Adipose Triglyceride Lipase (ATGL). Subsequent characterization using cultured cells and mutant mouse lines has demonstrated that ATGL acts as the rate-limiting enzyme in lipolysis by catalyzing the first step of triglyceride breakdown. In further research, the Zechner laboratory identified CGI-58 as a co-activator of ATGL essential to triglyceride breakdown in many cell types.  Recent work in our laboratory has identified a protein named G0S2 as a potent inhibitor of ATGL, providing a new piece to the complex lipolysis puzzle. G0S2 interacts directly with ATGL to attenuate its lipase activity, both in the absence and in the presence of CGI-58. Knockdown of endogenous G0S2 using siRNA accelerates basal and stimulated lipolysis in adipocytes, whereas overexpression of G0S2 using recombinant adenovirus diminishes the rate of lipolysis in both adipocytes and adipose tissue explants. Additionally, G0S2 expression in adipocytes is reciprocally regulated by insulin and lipolytic stimulators such as β-adrenergic agonists and TNF-α, implicating a potential mechanism for the efficient hormonal regulation of triglyceride hydrolysis.

As usual, new insights raise many new questions. For example, what is the biochemical mechanism by which G0S2 inhibits ATGL? How does G0S2 work coordinately with other regulatory components such as the perilipin/ADRP/TIP47 (PAT) proteins in the lipolytic proteome? What is the in vivo physiologic relevance of G0S2 in modulating adipose lipolysis? In diet-induced obesity, does G0S2 expression in adipose tissue alter thereby contributing to elevated plasma fatty acid level and insulin resistance? We are currently pursuing answers to all these important questions using a wide variety of experimental approaches ranging from biochemistry, molecular and cellular biology to in vivo metabolic measurements. Our model systems include cultured and freshly isolated primary adipocytes and fat tissue explants as well as genetically engineered animals.

Second, we have had a long-standing interest in the role of integrin receptors in adipocyte differentiation. We previously identified a critical switch in gene activity from integrin α5 to integrin α6 during adipocyte differentiation.  That switch allows preadipocytes to cease dividing and cluster, forming bona fide adipocytes. Our current efforts are directed at manipulating these two integrins in cell culture and animal models, and examining the effects on the formation of adipocytes and the gain of fat tissue mass in diet-induced obesity. 

Together, these studies may generate new insights into the hormonal and nutritional regulation of triglyceride mobilization and fat tissue mass, and the potential roles for their respect alterations in the development and progression of obesity and metabolism syndrome.

Representative publications:

1. Liu, J.; Wu, J.; Oliver, C.J.; Shenolikar, S.; Brautigan, D.L. "Mutations of the serine phosphorylated in the protein type-1 phosphatase binding motif in the skeletal muscle glycogen-targeting subunit." Biochemical Journal. 2000, 346: 77-82.
2. Liu, J.; Brautigan, D.L. "Insulin stimulated phosphorylation of the protein phosphatase-1 striated muscle glycogen-targeting subunit and activation of glycogen synthase." Journal of Biological Chemistry. 2000, 275: 15940-15947.
3. Liu, J.; Brautigan, D.L. "Glycogen synthase association with the striated muscle glycogen-targeting subunit of protein phosphatase-1." Journal of Biological Chemistry. 2000, 275: 26074-26081.
4. Liu, J.; Prickett, T.D.; Elliott, E.; Meroni, G.; Brautigan, D.L. "Phosphorylation and microtubule association of the Opitz syndrome protein mid-1 is regulated by protein phosphatase 2A via binding to the regulatory subunit alpha 4."  Proceedings of the National Academy of Sciences of the United States of America. 2001, 98: 6650-6655.
5. Liu, J.; Kimura, A.; Baumann, C.A.; Saltiel, A.R. "APS mediates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes.” Molecular and Cellular Biology 2002, 22: 3599-3609.
6. Liu, J.; DeYoung, S.M.; Hwang, J.B.; O'Leary, E.E.; Saltiel, A.R. “The roles of Cbl-b and c-Cbl in insulin-stimulated glucose transport.” Journal Biological Chemistry, 2003, 278: 36754-36762.
7. Hu, J.; Liu, J.; Ghirlando, R.; Saltiel, A.R.; Hubbard, S.R. “Structural Basis for Recruitment of the Adapter Protein APS to the Activated Insulin Receptor.”  Molecular Cell, 2003, 12: 1379-1389.
8. Liu, J.; DeYoung, S.M.; Zhang, M.; Dold, L.D.; Saltiel, A.R. “The SPFH domain of flotillin-1 contains distinct sequences that direct plasma membrane localization and protein interactions in 3T3-L1 adipocytes.”  Journal Biological Chemistry, 2005, 280: 16125-16134.
9. Liu, J.; DeYoung, S.M.; Zhang, M.; Cheng, A., Saltiel, A.R. “Changes in integrin expression during adipocytes differentiation.” Cell Metabolism, 2005, 3: 165-177.
10. Zhang, M.*; Liu, J.*; Cheng, A; DeYoung, S.M.; Chen, X.; Dold, L.D; Saltiel, A.R. “CAP interacts with cytoskeletal proteins and regulates adhesion-mediated ERK activation and motility.” EMBO Journal, 2006, 25: 5284-5293.
11. (*These authors contributed equally to the work.)
12. White, J.; Guerin, T.; Swanson, H.; Post, S.; Zhu, H.; Gong, M.C.; Liu, J.; Everson, W.V.; Li, X.A.; Graf, G.A.; Ballard, H.O.; Ross, S.A.; Smart, E.J. “Diabetic HDL associated myristic acid inhibits acetylcholine induced NO generation by preventing the association of endothelial NO synthase with calmodulin.”  American Journal of Physiology—Cell Physiology, 2007, 25=94:C295-305.
13. Zhang, M.; Liu, J.; Cheng, A.; DeYoung, S.M.; Saltiel, A.R. “Identification of CAP as a costameric protein that interacts with filamin C.” Molecular Biology of the Cell, 2008, 18: 4731-4740.
14. Yang, X; Lu, X; Liu, J. “Identification of liver-specific splicing variant of CGI-58, the causative gene for Chanarin-Dorfman Syndrome.” FEBS Letters, 2010, 584: 903-910. Yang, X; Lu, X; Lombès M.; Rha G.B.; Chi Y.I.; Guerin T.M.; Smart, E.J.; Liu, J. “The G0/G1 switch gene 2 attenuates adipose lipolysis through association with Adipose Triglyceride Lipase.” Cell Metabolism, 2010, 11: 194-205.