Jun Liu, M.D., Ph.D., and colleagues in his lab are primarily interested in the relationship between dysregulation of lipid metabolism and the pathogenesis of metabolic diseases such as obesity, fatty liver, insulin-resistant diabetes and cancer.
Fatty acids (FAs) are the basic building blocks of membrane lipids and the most efficient fuel for energy production. While a constant supply of FAs is required to maintain cellular homeostasis, FAs in excess can disrupt membrane structures, generate harmful metabolites and perturb the cellular redox balance. Protection of cells against the so-called lipotoxicity is dependent on the efficient storage of FAs as triglycerides (TGs), a process that requires a carefully controlled balance between synthesis of TGs from FAs and lipolytic breakdown of TGs into FAs.
By employing cutting-edge biochemical, cell biological and animal metabolic phenotyping techniques, Dr. Liu's lab strives to gain a deeper understanding of how lipolysis is regulated on cellular, tissue and whole body levels. Model systems include cultured and freshly isolated primary cells, tissue explants, and genetically engineered animals.
Lipolytic enzymes and regulators. Previous studies have established adipose tissue triglyceride lipase (ATGL) as the key enzyme for intracellular lipolysis. Shedding light on the basic mechanisms that regulate ATGL-catalyzed lipolysis, Dr. Liu's group has recently identified two small proteins, namely G0/G1 Switch Gene 2 (G0S2) and Hypoxia-Inducible Gene 2 (HIG2), as selective endogenous inhibitors of ATGL. G0S2 exhibits an FA-responsive expression pattern, and is critical for regulating FA flux to mitochondria for oxidation in adipose tissue and liver. HIG2, on the other hand, acts to protect cells in low-oxygen environments against oxidative stress and damage.
Collectively, the evidence obtained by Dr. Liu's lab implicates the modulation of ATGL by endogenous inhibitors as a unifying mechanism that promotes cellular adaptation to both nutritional and hypoxic stress conditions. The lab is currently focused on studying the structural elements in G0S2 and HIG2 that are responsible for ATGL inhibition, the pathophysiologic relevance of G0S2 and HIG2 under different nutritional and hormonal conditions, and the feasibility of targeting ATGL inhibitory mechanisms for therapeutic development.
Hormonal signaling to adipose lipolysis. Another area of interest in Dr. Liu's lab is the hormonal regulation of adipose lipolysis. While lipolysis in white adipose tissue supplies free FAs as an energy source to other tissues and organs, lipolysis in brown and beige adipose tissue is vital for heat production. In response to fasting or cold stress, adipocyte lipolysis is mainly stimulated by β–adrenergic hormone norepinephrine. However, emerging evidence also suggests an important role by the pituitary-secreted adrenocorticotropic hormone (ACTH). In the adrenal gland, ACTH is known to stimulate glucocorticoid production through activation of the melanocortin 2 receptor (MC2R).
Work by Dr. Liu's lab lately demonstrated that the ACTH/MC2R signaling triggers lipolysis in mature adipocytes, and down-regulation of the MC2R accessory protein MRAP in obesity contributes to metabolic dysfunction in adipose tissue. In particular, researchers identified the GαS protein as a novel MRAP binding partner, and provided evidence that the MRAP/GαS association is necessary for mediating the lipolytic action of ACTH/MC2R. The current research focus is to further explore the functional involvement of the ACTH/MC2R/MRAP/GαS pathway in adipocytes, and how its activation may antagonize the deleterious effects of glucocorticoids for maintaining the whole-body energy balance.
Significance to patient care
The ultimate goal of Dr. Liu's research is to discover new lipid regulators that are important for various metabolic diseases with the hope of translating this work from bench to the bedside. A better understanding of cellular mechanisms and metabolic functions will lead to better treatment outcomes for diseases such as obesity, cardiovascular diseases, type 2 diabetes, fatty liver disease and cancer.