Abstract
Sitosterolemia is a lipid disorder characterized by the accumulation of dietary xenosterols in plasma and tissues caused by mutations in either ABCG5 or ABCG8. ABCG5 ABCG8 encodes a pair of ABC half transporters that form a heterodimer (G5G8), which then traffics to the surface of hepatocytes and enterocytes and promotes the secretion of cholesterol and xenosterols into the bile and the intestinal lumen. We review the literature from the initial description of the disease, the discovery of its genetic basis, current therapy, and what has been learned from animal, cellular, and molecular investigations of the transporter in the twenty years since its discovery. The genomic era has revealed that there are far more carriers of loss of function mutations and likely pathogenic variants of ABCG5 ABCG8 than previously thought. The impact of these variants on G5G8 structure and activity are largely unknown. We propose a classification system for ABCG5 ABCG8 mutants based on previously published systems for diseases caused by defects in ABC transporters. This system establishes a framework for the comprehensive analysis of disease-associated variants and their impact on G5G8 structure–function.
Highlights
The discovery of ezetimibe as the inhibitor of Neiman–Pick C-1-Like 1 (NPC1L1), and cholesterol absorption was a breakthrough in the clinical management of sitosterolemia [24,25]
This complicates interpretations of ABCG5 ABCG8 physiology with respect to cholesterol metabolism, as phytosterols are known to produce a myriad of biological effects, including disruptions of sterol sensing by sterol receptor element binding protein 2 (SREBP-2), LXR, and the bile acid receptor [40,41,42,43]
The last twenty years have revealed a great deal about the role of ABCG5 ABCG8 in cholesterol metabolism and in the defense against the accumulation of dietary xenosterols
Summary
Three independent mouse models of sitosterolemia have been developed which lack functional Abcg, Abcg, or both half transporters [29,30,31]. The available data indicates that the presentation of sitosterolemia in both humans and rodent models is a function of the type and abundance of xenosterols present in the diet that accumulates in plasma and tissues This complicates interpretations of ABCG5 ABCG8 physiology with respect to cholesterol metabolism, as phytosterols are known to produce a myriad of biological effects, including disruptions of sterol sensing by sterol receptor element binding protein 2 (SREBP-2), LXR, and the bile acid receptor (farnesoid X receptor, FXR NR1H4) [40,41,42,43]. Given its abundant expression in the intestinal epithelium, its role in biliary cholesterol secretion, and the common pathway for cholesterol and phytosterol absorption (NPC1L1), it stands to reason that G5G8 would oppose cholesterol absorption Studies in both humans and mice have produced inconsistent results. The extent to which other enzymes contribute to a G5G8-independent pathway, and if such a pathway might be targeted to increase biliary cholesterol secretion remains unknown
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