The novel intracellular protein CREG inhibits hepatic steatosis, obesity and insulin resistance

Abstract

Cellular repressor of E1A-stimulated genes (CREG), a novel cellular glycoprotein, has been identified as a suppressor of various cardiovascular diseases (CVDs) because of its capacity to reduce hyperplasia, maintain vascular homeostasis, and promote endothelial restoration. However, the effects and mechanism of CREG in metabolic disorder and hepatic steatosis remain unknown. Here, we report that hepatocyte-specific CREG deletion dramatically exacerbates high fat diet (HFD) and leptin deficiency-induced (ob/ob) adverse effects such as obesity, hepatic steatosis and metabolic disorders, whereas a beneficial effect is conferred by CREG overexpression. Additional experiments demonstrated that JNK1 but not JNK2 is largely responsible for the protective effect of CREG on the above mentioned pathologies. Notably, JNK1 inhibition strongly prevents the adverse effects of CREG deletion on steatosis and related metabolic disorders. Mechanistically, CREG directly interacts with apoptosis signal-regulating kinase1 (ASK1) and inhibits its phosphorylation, thereby blocking the downstream MKK4/7-JNK1 signaling pathway and leading to significantly alleviated obesity, insulin resistance and hepatic steatosis. Importantly, dramatically reduced CREG expression and hyper-activated JNK1 signaling was observed in the livers of NAFLD patients, thus suggesting that CREG might be a promising therapeutic target for NAFLD and related metabolic diseases. Conclusion: The results of our study provide the first evidence that CREG is a robust suppressor of hepatic steatosis and metabolic disorders through its direct interaction with ASK1 and the resultant inactivation of ASK1-JNK1 signaling. This study offers new insights into NAFLD pathogenesis and its complicated pathologies, such as obesity and insulin resistance, and paves the way for disease treatment through targeting CREG. This article is protected by copyright. All rights reserved.

http://ift.tt/2qlTLLL