title: Nogo-B receptor deficiency increases liver X receptor alpha nuclear translocation and hepatic lipogenesis through an adenosine monophosphate-activated protein kinase alpha-dependent pathway.
abstract: 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.
  
  
  
  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).
authors.affiliation: Departments of Surgery and Pathology, Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI.|State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
authors.forename: Wenquan
authors.initials: W
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
authors.forename: Yuanli
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Departments of Surgery and Pathology, Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Ujala
authors.initials: U
authors.lastname: Rana
authors.affiliation: Department of Pediatrics, Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Ru-Jeng
authors.initials: RJ
authors.lastname: Teng
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Departments of Surgery and Pathology, Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Departments of Surgery and Pathology, Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Baofeng
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Blood Center of Wisconsin, Milwaukee, WI.
authors.forename: Jamie
authors.initials: J
authors.lastname: Foeckler
authors.affiliation: Blood Center of Wisconsin, Milwaukee, WI.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Weiler
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Kallinger
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thomas
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI.
authors.forename: Kezhong
authors.initials: K
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China. hanjihong2015@hfut.edu.cn.|College of Biomedical Engineering, Hefei University of Technology, Hefei, China. hanjihong2015@hfut.edu.cn.
authors.forename: Jihong
authors.initials: J
authors.lastname: Han
authors.affiliation: Departments of Surgery and Pathology, Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI. qmiao@mcw.edu.
authors.forename: Qing Robert
authors.initials: QR
authors.lastname: Miao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000818:Animals; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors / Q000378:metabolism*; D051379:Mice; D011956:Receptors, Cell Surface / Q000172:deficiency*; D015398:Signal Transduction
chemical_list: D000071518:Liver X Receptors; C512615:Nogo-B receptor, mouse; D011956:Receptors, Cell Surface; D055372:AMP-Activated Protein Kinases