Abstract 33: Deficiency of Nogo-B Receptor Promotes the Nuclear Translocation of Liver X Receptor Alpha and Hepatic Lipogenesis
The Nogo-B receptor (NgBR) was identified as a receptor necessary for Nogo-B induced morphogenesis of endothelial cells and developmental angiogenesis in Zebrafish. NgBR also is essential for the stability of NPC2 as well as NPC2 dependent cholesterol trafficking under serum-free condition. Here, we reported the novel roles of NgBR in regulating hepatic lipogenesis in vivo via NPC2-independnet pathways. Our results showed that either NgBR knockdown in hepatocyte under serum presence condition in vitro or NgBR knockout in mouse liver in vivo do not decrease NPC2 levels or increase NPC2-dependent intracellular cholesterol amount. However, NgBR deficiency resulted in significant increase of free fatty acid and triglyceride in hepatocyte in vitro and in mouse livers in vivo. Mechanistically, NgBR deficiency induces the nuclear translocation of the liver X receptor alpha (LXRα) so as to increase the expression of its downstream target genes involved in fatty acid synthesis, such as the sterol regulatory element binding protein-1 (SREBP-1) and fatty acid synthesis (FAS). Liver X receptor alpha (LXRα) is a member of nuclear receptor superfamily and one of master regulators for lipid metabolism. Real-time PCR results further showed that NgBR deficiency increased expression of LXRα-regulated gene such as ABCA1, SCD, ABCG8, SREBP1 and FAS, which are involved in lipid efflux and metabolism. LXRα knockdown by transient transfection of LXRα siRNA abolished NgBR deficiency caused accumulation of free fatty acid and triglyceride in stable hepatic cell lines and in the livers of NgBR knockout mice fed with the high fat diet. These observations demonstrated that NgBR deficiency induces lipid accumulation via the activation of LXRα pathway. It suggests that NgBR is essential for preventing hepatic steatosis.
Author Disclosures: W. Hu: None. W. Zhang: None. U. Rana: None. M. Bordas: None. B. Zhao: None. J. Han: None. Q. Miao: None.
- © 2014 by American Heart Association, Inc.