title: Acceleration of biliary cholesterol secretion restores glycemic control and alleviates hypertriglyceridemia in obese db/db mice.
abstract: OBJECTIVE
  Recent studies support a role for cholesterol in the development of obesity and nonalcoholic fatty liver disease. Mice lacking the ABCG5 ABCG8 (G5G8) sterol transporter have reduced biliary cholesterol secretion and are more susceptible to steatosis, hepatic insulin resistance, and loss of glycemic control when challenged with a high-fat diet. We hypothesized that accelerating G5G8-mediated biliary cholesterol secretion would correct these phenotypes in obese mice.
  
  
  RESULTS
  Obese (db/db) male and their lean littermates were administered a cocktail of control adenovirus or adenoviral vectors encoding ABCG5 and ABCG8 (AdG5G8). Three days after viral administration, measures of lipid and glucose homeostasis were determined, and tissues were collected for biochemical analyses. AdG5G8 increased biliary cholesterol and fecal sterol elimination. Fasting glucose and triglycerides declined, and glucose tolerance improved in obese mice expressing G5G8 compared with mice receiving control adenovirus. These changes were associated with a reduction in phosphorylated eukaryotic initiation factor 2α and c-Jun N-terminal kinase in liver, suggesting alleviation of endoplasmic reticulum stress. Phosphorylated insulin receptor and protein kinase B were increased, indicating restored hepatic insulin signaling. However, there was no reduction in hepatic triglycerides after the 3-day treatment period.
  
  
  CONCLUSIONS
  Accelerating biliary cholesterol secretion restores glycemic control and reduces plasma triglycerides in obese db/db mice.
authors.affiliation: From the Department of Pharmaceutical Sciences, Graduate Center for Nutritional Sciences and Saha Cardiovascular Research Center, University of Kentucky, Lexington (K.S., Y.W., X.L., J.D.L., G.A.G.); Department of Neuroscience, Universidad Central del Caribe, Bayamon, Puerto Rico (N.S.S.); Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas (J.L.); and Department of Clinical Laboratories, Jinshan Branch of the Sixth People's Hospital of Shanghai, Shanghai, China (S.L.).
authors.forename: Kai
authors.initials: K
authors.lastname: Su
authors.forename: Nadezhda S
authors.initials: NS
authors.lastname: Sabeva
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Liu
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Lester
authors.forename: Jingjing
authors.initials: J
authors.lastname: Liu
authors.forename: Shuang
authors.initials: S
authors.lastname: Liang
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Graf
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001646:Bile / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood*; D004195:Disease Models, Animal; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D018014:Gene Transfer Techniques; D020022:Genetic Predisposition to Disease; D015316:Genetic Therapy; D005822:Genetic Vectors; D015228:Hypertriglyceridemia / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000628:therapy*; D007413:Intestinal Mucosa / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000097:blood / Q000150:complications* / Q000235:genetics; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D013997:Time Factors; D014280:Triglycerides / Q000097:blood*
chemical_list: D018528:ATP-Binding Cassette Transporters; D015415:Biomarkers; D001786:Blood Glucose; D015852:Eukaryotic Initiation Factor-2; D014280:Triglycerides; D002784:Cholesterol; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases
keywords: bile; cholesterol; insulin resistance; liver steatosis; obesity