Abstract
The ABCG5/ABCG8 (G5G8) sterol transporter opposes the accumulation of dietary xenosterols but is also the primary mediator of biliary cholesterol secretion. In humans and in mouse models of disrupted biliary cholesterol secretion, fecal neutral sterols (FNSs) remain constant, indicating the presence of an alternate pathway for cholesterol excretion. Transintestinal cholesterol elimination or excretion (TICE) is thought to compensate for biliary disruptions and G5G8 insufficiency. We sought to measure the compensatory increase in intestinal cholesterol secretion and provide mechanistic insight for how TICE maintains sterol balance in the absence of hepatic G5G8. Differences were not observed in FNSs between control, acute, and chronic liver-specific G5G8-deficient mice (G5G8LKO). Cholesterol content did not differ at any point along the intestinal tract between genotypes. We also observed no change in the expression of apical or basolateral sterol transporters in the proximal small intestine. We then measured biliary and intestinal cholesterol secretion rates using cholesterol-free and cholesterol-enriched bile acid micelles as acceptors. While biliary cholesterol secretion was reduced, the intrinsic rate of intestinal cholesterol secretion did not differ between genotypes. G5G8LKO and whole-body G5G8-deficient mice were challenged with a cholesterol-containing diet. While control mice upregulate FNS excretion, G5G8-independent mechanisms fail to maintain fecal sterol excretion and oppose the accumulation of cholesterol in liver and plasma. These studies indicate that while G5G8-independent mechanisms can mediate cholesterol excretion, TICE is not upregulated in response to a loss of hepatic G5G8 and is unable to compensate for hepatic or whole-body G5G8 deficiency in response to dietary cholesterol in mice.
Document Type
Article
Publication Date
2025
Digital Object Identifier (DOI)
https://doi.org/10.1016/j.jlr.2025.100902
Funding Information
This work was supported in part by grants from the National Institutes of Health 5R01DK113625 (to G. A. G.), K01DK128022 (to R. N. H.), UL1TR001998 (to R. N. H.), and an American Heart Association Career Development Award 23CDA1051959 (to R. N. H.). The project was also supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through grant UL1TR001998. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Repository Citation
Anspach, Garrett B.; Kaur, Rupinder; Chauhan, Isha; Savage, Erika L.; Poole, Brittney; Noffsinger, Victoria P.; Fu, Xiaoming; Wang, Zeneng; Voy, Clairity; Temel, Ryan E.; Gordon, Scott M.; Helsley, Robert N.; and Graf, Gregory A., "ABCG5/ABCG8-independent mechanisms fail to maintain sterol balance in mice fed a high-cholesterol diet" (2025). Saha Cardiovascular Research Center Faculty Publications. 98.
https://uknowledge.uky.edu/cvrc_facpub/98
Notes/Citation Information
© 2025 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).