We recently identified a previously uncharacterized 38 kD protein, which contains an apolipoprotein-like domain and is specifically expressed in adipose tissue. Due to lack of signal sequence, however, the protein is not secreted. Rather, we found that it is localized to lipid droplets (LD), making this protein a newly discovered adipose-specific LD-associated protein. We found that this new LD-associated protein is found at the LD contact site and promotes lipid transfer. In addition, we detected direct interaction with Fsp27 (also called CideC). Furthermore, expression of the gene coding for this apolipoprotein-like protein is very low in adipose tissue of fasted mice, but is increased upon feeding, especially when fed a high fat diet. We also found it to be overexpressed in both genetic and diet induced obesity, suggesting its contribution to adiposity. We have generated transgenic mice for overexpression in adipose tissue, as well as global KO mice by using CRISPR-Cas9 system. Our transgenic mice showed a greatly increased white adipose tissue (WAT) mass with enlarged adipocytes in WAT, having decreased lipolysis without significant changes in lipogenesis. Conversely, our global KO mice showed a substantially diminished adipose tissue mass with smaller adipocyte size with higher lipolysis that protected mice from diet induced obesity. Our long-term goal is to understand the molecular details and physiological significance of the function of this protein as a LD-associated protein to promote LD growth/lipid transfer and TAG storage in WAT.
Aim 1 is to examine regulation of lipid transfer by ApoL6.
Aim 2 is to examine regulation of lipolysis by this protein. Finally, Aim 3 is to examine its role in vivo by performing loss- and gain-of function studies in mice. Overall, the proposed research will define the role of this newly discovered LD protein on LD growth/lipid transfer and lipolysis in WAT. This research may not only help to better understand adipose LD physiology but also provide future therapeutic targets for obesity/diabetes.
Obesity is a major health problem associated with metabolic syndrome and type 2 diabetes and the control of adiposity is a top priority in managing these diseases. Proteins that are associated with lipid droplets present in adipose tissue play important role in LD growth/lipid transfer as well as triglyceride storage and metabolism. Understanding the molecular details for the function of this new lipid droplet associated protein may provide novel therapeutic targets for obesity/diabetes.
