Cidea Promotes Hepatic Steatosis By Sensing Dietary Fatty Acids

Hepatic steatosis is characterized by the accumulation of excess amounts ofhepatic neutral lipids, resulting from abnormal hepatic lipid metabolism. Hepaticsteatosis could lead to liver fibrosis and cancer. Dietary saturated fatty acid couldcause liver steatosis. However, the identities of the molecules that sense the effects ofdietary saturated fatty acids to initiate hepatic steatosis remain unclear.The cell death-inducing DNA fragmentation factor (DFF)-like effector(CIDE) proteins (Cidea, Cideb, and Cidec [or Fsp27, the homolog of Cidec inthe mouse]) are lipid droplet (LD)-associated proteins that have emerged asimportant regulators of lipid storage and the formation of large LDs inadipocytes and hepatocytes. Here, we observed that Cidea expression wasmarkedly increased in human and mouse hepatic steatosis. Overexpression ofCidea in mouse liver cell line AML12or in mouse liver resulted in increasedlipid accumulation and the formation of larger lipid droplet. In contrast,Cidea-/-mice had decreased lipid accumulation and alleviated hepatic steatosiscaused by high-fat-diet feeding or a leptin deficiency. Futhermore, theknockdown of Cidea in the livers of ob/ob mice resulted in dramatic reducedhepatic lipid accumulation and smaller lipid droplet. In addition, we observedthat Cidea expression was specifically increased in hepatocytes in response tosaturated fatty acid intake; this upregulation was likely mediated by SREBP1c.We also observed that the stability of the Cidea protein in hepatocytes wassignificantly increased in response to fatty acid treatment. Overall, we haveestablished a novel pathway for FA-induced hepatic steatosis that is mediatedby Cidea.