Acceleration of biliary cholesterol secretion restores glycemic control and alleviates hypertriglyceridemia in obese db/db mice

Kai Su, Nadezhda S. Sabeva, Yuhuan Wang, Xiaoxi Liu, Joshua D. Lester, Jingjing Liu, Shuang Liang, Gregory A. Graf

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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. APPROACH AND 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.

Original languageEnglish
Pages (from-to)26-33
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number1
StatePublished - Jan 2014


  • Bile
  • Cholesterol
  • Insulin resistance
  • Liver steatosis
  • Obesity

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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