Nogo-B receptor deficiency increases liver X receptor alpha nuclear translocation and hepatic lipogenesis through an adenosine monophosphate-activated protein kinase alpha-dependent pathway. Hepatology 2016 Nov;64(5):1559-1576
Date
10/22/2016Pubmed ID
27480224Pubmed Central ID
PMC5074877DOI
10.1002/hep.28747Scopus ID
2-s2.0-84983371299 (requires institutional sign-in at Scopus site) 28 CitationsAbstract
UNLABELLED: Nogo-B receptor (NgBR) was identified as a specific receptor for binding Nogo-B and is essential for the stability of Niemann-Pick type C2 protein (NPC2) and NPC2-dependent cholesterol trafficking. Here, we report that NgBR expression levels decrease in the fatty liver and that NgBR plays previously unrecognized roles in regulating hepatic lipogenesis through NPC2-independent pathways. To further elucidate the pathophysiological role of NgBR in mammals, we generated NgBR liver-specific knockout mice and investigated the roles of NgBR in hepatic lipid homeostasis. The results showed that NgBR knockout in mouse liver did not decrease NPC2 levels or increase NPC2-dependent intracellular cholesterol levels. However, NgBR deficiency still resulted in remarkable cellular lipid accumulation that was associated with increased free fatty acids and triglycerides in hepatocytes in vitro and in mouse livers in vivo. Mechanistically, NgBR deficiency specifically promotes the nuclear translocation of the liver X receptor alpha (LXRα) and increases the expression of LXRα-targeted lipogenic genes. LXRα knockout attenuates the accumulation of free fatty acids and triglycerides caused by NgBR deficiency. In addition, we elucidated the mechanisms by which NgBR bridges the adenosine monophosphate-activated protein kinase alpha signaling pathway with LXRα nuclear translocation and LXRα-mediated lipogenesis.
CONCLUSION: NgBR is a specific negative regulator for LXRα-dependent hepatic lipogenesis. Loss of NgBR may be a potential trigger for inducing hepatic steatosis. (Hepatology 2016;64:1559-1576).
Author List
Hu W, Zhang W, Chen Y, Rana U, Teng RJ, Duan Y, Liu Z, Zhao B, Foeckler J, Weiler H, Kallinger RE, Thomas MJ, Zhang K, Han J, Miao QRAuthors
Ru-Jeng Teng MD Professor in the Pediatrics department at Medical College of WisconsinMichael J. Thomas PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AMP-Activated Protein KinasesAnimals
Fatty Liver
Female
Lipogenesis
Liver
Liver X Receptors
Mice
Receptors, Cell Surface
Signal Transduction
