CIDE-A is expressed in liver of old mice and in type 2 diabetic mouse liver exhibiting steatosis

Microarray analysis identified CIDE-A as the most differentially expressed gene as a function of age. Mice fed a high fat diet developed hyperinsulinemia, hyperglycemia and liver steatosis, all features of the human metabolic syndrome. Increased CIDE-A expression was observed in type 2 diabetic liver and the elevated CIDE-A expression could be reversed by weight loss and normalization of plasma insulin. Also, CIDE-A expression was found to be correlated with hepatic lipid accumulation.The corresponding increase in CIDE-A expression with hyperinsulinemia and liver steatosis suggests a novel pathway for lipid accumulation in the liver.Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of liver disease and is estimated to affect 10 to 24% of the general population in western nations [1]. While NAFLD is a serious problem, effective treatments are still lacking. NAFLD is characterized by a wide spectrum of liver damage ranging from simple steatosis to steatohepatitis (NASH) to advanced fibrosis and cirrhosis [2]. Hepatic steatosis is caused by lipid accumulation within hepatocytes and is a relatively benign condition. However, steatosis combined with necro-inflammatory activity may progress to end-stage liver disease [3-7]. The higher prevalence of NAFLD in persons with obesity, hyperinsulinemia or type 2 diabetes suggests that elevated circulating fatty acid concentrations caused by insulin resistance and increased adipocyte lipolysis plays a pivotal role in the development of this syndrome [1,8].CIDE-A (cell-death-inducing DFF45-like effector-A) is a member of a family of proapoptotic proteins that includes CIDE-B and CIDE-3/FSP27 [9-11]. Whereas CIDE-A is capable of inducing apoptosis, CIDE-A also plays a role in regulating energy balance and lipid metabolism [12]. CIDE-A gene disrupted mice (CIDE-A -/-) have a lean phenotype and are resistant to diet-induced obesity and possibly diabetes [12]. CIDE-A also interacts and inhibits uncoupling prot