GRP78 rescues the ABCG5 ABCG8 sterol transporter in db/db mice

Yuhuan Wang, Kai Su, Nadezhda S. Sabeva, Ailing Ji, Deneys R. Van Der Westhuyzen, Fabienne Foufelle, Xia Gao, Gregory A. Graf

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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. Methods and 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.

Original languageEnglish
Pages (from-to)1435-1443
Number of pages9
JournalMetabolism: Clinical and Experimental
Issue number11
StatePublished - Nov 2015

Bibliographical note

Funding Information:
This work was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (Graf: R01DK080874 and R01DK100892 ) and the National Institute of General Medical Sciences ( 8 P20 GM103527-05 ) of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2015 Elsevier Inc.


  • Chaperones
  • Cholesterol
  • Leptin
  • Lipids and lipoprotein metabolism
  • Obesity

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology


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