While liver steatosis and its associated diseases represent an ever increasing health problem, the key pathways and metabolic processes involved in the development of this disease are not fully understood and effective therapies are lacking. In this report, we describe a new pathway that may be involved in liver steatosis. We demonstrate that CIDE-A is expressed in liver of old mice. In fact, DNA microarray analysis indicates that CIDE-A is the most differentially expressed liver gene between young and older mice (38-fold increase). The increased expression of CIDE-A may not be due solely to increased age per se, but more likely a consequence of increased insulin resistance in the mice at older ages [30
]. Insulin resistance is a common occurrence in aging individuals and is believed to be caused by increased adiposity rather than the aging process [31
]. CIDE-A expression is also increased in a model of diet-induced type 2 diabetes. Increased CIDE-A expression was confirmed by Northern and immunoblot analyses. Elevated CIDE-A expression can be reversed by weight loss and normalization of plasma insulin. Also, CIDE-A expression was found to be correlated with hepatic lipid accumulation.
Previous reports have indicated that human and mouse CIDE-A are expressed in several tissues such as BAT, WAT, heart, lymph node, thymus, skeletal muscle and is localized to the mitochondria [9
]. In another study, CIDE-A-deficient mice were found to have a lean phenotype and are resistant to obesity [12
]. We believe that CIDE-A expression was not previously detected in liver due to the use of tissue from an inappropriate age or condition. Our data would suggest that human liver from older, insulin resistant or diabetic individuals may express this protein.
This study has identified CIDE-A as another potential mediator of lipid accumulation in liver hepatocytes. A recent study has proposed a human-specific role for CIDE-A in lipolysis and metabolic complications [15
]. The previous study demonstrated that CIDE-A is expressed in human WAT with its expression decreased twofold in obese humans and normalized after weight loss. Reduced CIDE-A expression results in increased TNF-α secretion and basal lipolysis in subcutaneous WAT [15
]. Increased TNF-α secretion also further decreases CIDE-A expression via TNF-α signaling through c-Jun NH2
-terminal kinase (JNK) [15
]. With this data, a model has emerged describing the role of CIDE-A in elevation of circulating FFA. Specifically, a decrease in CIDE-A expression results in increased TNF-α secretion resulting in increased lipolysis. The increased basal WAT lipolysis induced by low CIDE-A levels and elevated TNF-α secretion results in elevated levels of circulating fatty acid which can then be redirected to other tissues such as the liver. According to the model, increased CIDE-A expression and subsequent decreased TNF-α secretion would lead to decreased lipolysis and the accumulation of lipid within the tissue. Thus, increased CIDE-A expression in hepatocytes as a result of insulin resistance and type 2 diabetes may promote the uptake of increased circulating fatty acids released from WAT and lead to steatosis.
CIDE-A has been postulated to play a role in apoptosis suggesting the intriguing possibility that CIDE-A may play a role in apoptosis associated with liver steatosis and NAFLD. Disease progression from benign steatosis involves injury and an inflammatory response [4
]. While the cause of the injury is not understood, it is clear that cellular apoptosis represents one of the first responses to injury and is a prominent feature of NAFLD as well as other diseases such as viral hepatitis, alcohol-induced liver disease, cholestatic liver diseases and ischemia/perfusion injury [3
]. We did not, however detect increased apoptosis in CIDE-A expressing livers samples by TUNEL analysis and therefore believe that CIDE-A main function in the liver involves lipid metabolism.