Abstract 422: The Lipid Droplet Associated Protein CIDEC/Fsp27 is Regulated by PPARα and Prevents Hepatic Triglyceride Utilization
The cell death-inducing DFFA-like effector c (CIDEC; known as FSP27 or fat-specific protein 27 in rodents) is a lipid droplet (LD)-associated protein that is mainly expressed in white adipose tissue, where it promotes triglyceride storage. Fsp27 levels are undetectable in the livers of fed mice, but rise during fasting or under hepatosteatosis in both obese mice and patients. The Peroxisome Proliferator Activated Receptor α (PPARα) is a nuclear receptor that controls the fatty acid oxidative pathway. Hepatic PPARα signaling is activated physiologically during fasting, and pharmacologically by fibrates, a class of hypotriglyceridemic drugs. Here we show that CIDEC/Fsp27 is induced in primary hepatocytes and in the liver by synthetic PPARα agonists, and promoter reporter and ChIP assays identified CIDEC/Fsp27 as a conserved, direct PPARα target. Importantly, adenoviral-mediated shRNA silencing of hepatic Fsp27 resulted in a strong reduction of fasting-induced hepatosteatosis. Likewise, in vivo shRNA against Fsp27 resulted in decreased hepatic triglyceride contents in mice fed a high-fat diet, and in mice dosed with a PPARα agonist. Further studies in mouse primary hepatocytes showed that loss of Fsp27 activity enhanced PPARα-stimulated fatty acid oxidation. Collectively, our results highlight the physiological role of CIDEC/Fsp27 in hepatic triglyceride homeostasis. Additionally, these data suggest that patients taking fibrates likely have elevated levels of hepatic CIDEC, which may limit the efficient catabolism of hepatic triglycerides.
Author Disclosures: C. Langhi: None. A. Baldan: None.
- © 2014 by American Heart Association, Inc.