The overall goal of this grant is to determine the mechanism by which the ATP-binding cassette halftransporters, ABCG5 and ABCG8 (G5G8), mediate the transport of sterols across membranes. Previously, we discovered that mutations in either G5 or G8 cause sitosterolemia, which is characterized by the accumulation of plant sterols and cholesterol, and by premature coronary artery disease. We showed that G5 and G8 must heterodimerize in the endoplasmic reticulum (ER) prior to trafficking to the apical surfaces of hepatocytes and enterocytes, where the transporter secretes sterols into bile and the gut lumen, respectively. During the last funding period we developed in vivo and in vitro assays to assess the structural requirements for G5G8- mediated sterol transport.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL072304-12
Application #
8608575
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Liu, Lijuan
Project Start
2003-02-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Lee, Jyh-Yeuan; Kinch, Lisa N; Borek, Dominika M et al. (2016) Crystal structure of the human sterol transporter ABCG5/ABCG8. Nature 533:561-4
Wang, Jin; Mitsche, Matthew A; Lütjohann, Dieter et al. (2015) Relative roles of ABCG5/ABCG8 in liver and intestine. J Lipid Res 56:319-30
Mitsche, Matthew A; McDonald, Jeffrey G; Hobbs, Helen H et al. (2015) Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways. Elife 4:e07999
Stiles, Ashlee R; Kozlitina, Julia; Thompson, Bonne M et al. (2014) Genetic, anatomic, and clinical determinants of human serum sterol and vitamin D levels. Proc Natl Acad Sci U S A 111:E4006-14
Wang, Jin; Grishin, Nick; Kinch, Lisa et al. (2011) Sequences in the nonconsensus nucleotide-binding domain of ABCG5/ABCG8 required for sterol transport. J Biol Chem 286:7308-14
Rios, Jonathan; Stein, Evan; Shendure, Jay et al. (2010) Identification by whole-genome resequencing of gene defect responsible for severe hypercholesterolemia. Hum Mol Genet 19:4313-8
Wang, Jin; Zhang, Da-Wei; Lei, Ying et al. (2008) Purification and reconstitution of sterol transfer by native mouse ABCG5 and ABCG8. Biochemistry 47:5194-204