Abstract
Curcumin has been shown to have anti-obesity effects in animal studies. Although several molecular mechanisms of action have been reported, the initial or upstream molecular events remain to be revealed. In this study, we found that curcumin or heat shock treatment up-regulated the expression of adipose triglyceride lipase (ATGL) in Huh7 hepatoma cells, which resulted in acceleration of lipolysis. Interestingly, perturbation of protein homeostasis was seen in curcumin-treated cells, as detected by formation of numerous ubiquitinated proteins and conjugated proteins with p62 (SQSTM). Curcumin activated the protein expression of molecular chaperones, such as heat shock protein (HSP)40 and HSP70. Pre-treatment of the cells with 4-phenylbutyric acid, a chemical chaperone, suppressed proteo-stress induced by curcumin and reduced its lipolysis effect. Importantly, the cytotoxicity of curcumin was markedly alleviated when intracellular triglyceride was consumed by the polyphenol. Thus, energy supplementation from lipolysis may play substantial roles in adaptation and survival of curcumin-exposed cells. To support this notion, the cytotoxicity of curcumin was aggravated in ATGL-knockdown cells. Curcumin decreased intracellular ATP for activating AMP-activated protein kinase, which initiates catabolic pathways including ATGL-dependent lipolysis. Taken together, we propose a hypothesis that curcumin induces lipolysis to compensate for ATP reduction due to its proteo-stress effects.