title: GRP78 rescues the ABCG5 ABCG8 sterol transporter in db/db mice.
abstract: OBJECTIVE
  Mice lacking leptin (ob/ob) or its receptor (db/db) are obese, insulin resistant, and have reduced levels of biliary cholesterol due, in part, to reduced levels of hepatic G5G8. Chronic leptin replacement restores G5G8 abundance and increases biliary cholesterol concentrations, but the molecular mechanisms responsible for G5G8 regulation remain unclear. In the current study, we used a series of mouse models to address potential mechanisms for leptin-mediated regulation of G5G8.
  
  
  RESULTS
  We acutely replaced leptin in ob/ob mice and deleted hepatic leptin receptors in lean mice. Neither manipulation altered G5G8 abundance or biliary cholesterol. Similarly, hepatic vagotomy had no effect on G5G8. Alternatively, G5G8 may be decreased in ob/ob and db/db mice due to ER dysfunction, the site of G5G8 complex assembly. Overexpression of the ER chaperone GRP78 using an adenoviral vector restores ER function and reduces steatosis in ob/ob mice. Therefore, we determined if AdGRP78 could rescue G5G8 in db/db mice. As in ob/ob mice, AdGRP78 reduced expression of lipogenic genes and plasma triglycerides in the db/db strain. Both G5 and G8 protein levels increased as did total biliary cholesterol, but in the absence of changes in G5 or G8 mRNAs. The increase in G5G8 was associated with increases in a number of proteins, including the ER lectin chaperone, calnexin, a key regulator of G5G8 complex assembly.
  
  
  CONCLUSIONS
  Leptin signaling does not directly regulate G5G8 abundance. The loss of G5G8 in mice harboring defects in the leptin axis is likely associated with compromised ER function.
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Su
authors.affiliation: Department of Neuroscience, Universidad Central del Caribe, Bayamón, PR, USA.
authors.forename: Nadezhda S
authors.initials: NS
authors.lastname: Sabeva
authors.affiliation: Department of Internal Medicine and Molecular, University of Kentucky, Lexington, KY, USA; Department of Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.
authors.forename: Ailing
authors.initials: A
authors.lastname: Ji
authors.affiliation: Graduate Center for Nutritional Sciences, Saha Cardiovascular Research Center and Barnstable Brown Kentucky Diabetes and Obesity Center, Lexington, KY, USA; Department of Internal Medicine and Molecular, University of Kentucky, Lexington, KY, USA; Department of Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.
authors.forename: Deneys R
authors.initials: DR
authors.lastname: van der Westhuyzen
authors.affiliation: INSERM, UMR-S 872, Centre de Recherches des Cordeliers, 15 rue de L'école de Médecine, Paris, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Foufelle
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Xia
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA; Graduate Center for Nutritional Sciences, Saha Cardiovascular Research Center and Barnstable Brown Kentucky Diabetes and Obesity Center, Lexington, KY, USA. Electronic address: Gregory.Graf@uky.edu.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Graf
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000502:physiology*; D020738:Leptin / Q000235:genetics; D008074:Lipoproteins / Q000502:physiology*; D008297:Male; D051379:Mice
chemical_list: C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D020738:Leptin; D008074:Lipoproteins
keywords: Chaperones; Cholesterol; Leptin; Lipids and lipoprotein metabolism; Obesity