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 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 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 c-Jun N-terminal kinase 1 (JNK1) but not JNK2 is largely responsible for the protective effect of CREG on the aforementioned pathologies. Notably, JNK1 inhibition strongly prevents the adverse effects of CREG deletion on steatosis and related metabolic disorders. Mechanistically, CREG interacts directly with apoptosis signal-regulating kinase 1 (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, dramat...Continue Reading
References
Thioredoxin and HSP90 alpha modulate ASK1-JNK1/2 signaling in stressed hepatocytes of Mugil cephalus
Novel anti-apoptotic mechanism of A20 through targeting ASK1 to suppress TNF-induced JNK activation.
Citations
Creg in Hepatocytes Ameliorates Liver Ischemia/Reperfusion Injury in a TAK1-Dependent Manner in Mice
The secreted inhibitor of invasive cell growth CREG1 is negatively regulated by cathepsin proteases.
Exercise ameliorates insulin resistance and improves ASK1-mediated insulin signalling in obese rats.
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