The main research interest of Jun Liu, M.D., Ph.D., is in intracellular triglyceride lipolysis and lipid droplet turnover. By employing cutting-edge biochemical, cell biological and animal metabolic phenotyping techniques, along with various omics approaches, Dr. Liu's laboratory works vigorously to gain deeper insights into the fundamental mechanisms that govern lipolysis and how lipolytic dysregulation contributes to the development of various metabolic diseases.
- Fatty acids. Fatty acids (FAs) are the basic building blocks of membrane lipids, as well as the most efficient fuel for energy production. While a constant supply of FAs is required to maintain cellular homeostasis, FAs in excess exert cytotoxic effects by disrupting membrane structures, generating harmful metabolites and perturbing the cellular redox balance. Lipid droplets (LDs) are evolutionarily conserved organelles responsible for storing cellular surplus of FAs in esterified forms such as triglycerides. Efficient storage of FAs in LDs, which requires a carefully regulated balance between triglycerides synthesis and lipolysis, protects cells against lipotoxicity and oxidative stress.
Adipose triglyceride lipase (ATGL). Previous studies have established ATGL as the rate-limiting enzyme for intracellular lipolysis and a critical determinant of FA oxidation, as well as for the storage and production of toxic or essential lipid metabolites. Shedding light on the mechanisms that regulate ATGL-catalyzed lipolysis, Dr. Liu and colleagues have identified two small proteins, namely G0/G1 Switch Gene 2 (G0S2) and Hypoxia-Inducible Gene 2 (HIG2), as selective endogenous inhibitors of ATGL.
In mammals, G0S2 exhibits cyclical expression patterns between adipose tissue and liver that is responsive to FA flux and is critical for energy homeostasis in these two tissues. HIG2, which is abundantly expressed in solid tumors such as colorectal cancer and renal cell carcinoma, acts to protect cancer cells against oxidative stress in low-oxygen environments. Collectively, the evidence obtained thus far reveals that the modulation of ATGL lipolytic action by endogenous inhibitors is a unifying mechanism that promotes cell adaptation to both nutritional and hypoxic stress conditions.
Dr. Liu is currently focused on determining the structural elements in G0S2 and HIG2 that are responsible for LD localization and ATGL inhibition; elucidating the pathophysiologic relevance of G0S2 and HIG2 under different nutritional and hormonal conditions; and exploring the possibilities of targeting ATGL inhibitory mechanisms for therapeutic benefits. Model systems include cultured and freshly isolated primary cells, tissue explants, and genetically engineered cell lines and animals.
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.