ABCG5/G8: a structural view to pathophysiology of the hepatobiliary cholesterol secretion

Zein, Aiman A.; Kaur, Rajnish; Hussein, Toka O. K.; Graf, Gregory A.; Lee, Jyh-Yeuan

doi:10.1042/bst20190130

Cited by 49 publications

(48 citation statements)

References 80 publications

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“…Finally, we investigated the impact of ABC-G5/G8 on the levels of vitamin D metabolites in serum and tissues. The ABC-G5/G8 transporters are known to exert two common functions: the reverse intestinal transport of sterols [16] and the hepatic excretion of sterols into bile [17,45]. The significantly higher levels of serum lipids found in the Abcg5/g8 -/mice of the current study correspond to data on polymorphic variants of ABC-G5/G8 in humans that have been associated with elevated levels of circulating cholesterol and triglycerides [46,47].…”

Section: Discussionsupporting

confidence: 76%

“…ABC-G5 and ABC-G8 form a heterodimeric complex located in the brush-border membrane of enterocytes, the canalicular membranes of hepatocytes and the membranes of epithelial cells in the gallbladder [15]. They are responsible for the efflux of nonesterified sterols, such as plant sterols and, to a minor extent, cholesterol, from enterocytes back into the intestinal lumen (for review, see Zein et al [16]). In the liver, ABC-G5/G8 facilitates the excretion of sterols into bile [17].…”

Section: Introductionmentioning

confidence: 99%

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Vitamin D Status of Mice Deficient in Scavenger Receptor Class B Type 1, Cluster Determinant 36 and ATP-Binding Cassette Proteins G5/G8

et al. 2020

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Classical lipid transporters are suggested to modulate cellular vitamin D uptake. This study investigated the vitamin D levels in serum and tissues of mice deficient in SR-B1 (Srb1-/-), CD36 (Cd36-/-) and ABC-G5/G8 (Abcg5/g8-/-) and compared them with corresponding wild-type (WT) mice. All mice received triple-deuterated vitamin D3 (vitamin D3-d3) for six weeks. All knockout mice vs. WT mice showed specific alterations in their vitamin D concentrations. Srb1-/- mice had higher levels of vitamin D3-d3 in the serum, adipose tissue, kidney and heart, whereas liver levels of vitamin D3-d3 remained unaffected. Additionally, Srb1-/- mice had lower levels of deuterated 25-hydroxyvitamin D3 (25(OH)D3-d3) in the serum, liver and kidney compared to WT mice. In contrast, Cd36-/- and WT mice did not differ in the serum and tissue levels of vitamin D3-d3, but Cd36-/- vs. WT mice were characterized by lower levels of 25(OH)D3-d3 in the serum, liver and kidney. Finally, Abcg5/g8-/- mice tended to have higher levels of vitamin D3-d3 in the serum and liver. Major alterations in Abcg5/g8-/- mice were notably higher levels of 25(OH)D3-d3 in the serum and kidney, accompanied by a higher hepatic mRNA abundance of Cyp27a1 hydroxylase. To conclude, the current data emphasize the significant role of lipid transporters in the uptake, tissue distribution and activation of vitamin D.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Vitamin D Status of Mice Deficient in Scavenger Receptor Class B Type 1, Cluster Determinant 36 and ATP-Binding Cassette Proteins G5/G8

et al. 2020

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“…This heterodimer pumps excess cholesterol from the liver to the bile and ejects the toxic plant sterol, sitosterol, absorbed by the intestinal mucosa 109,126,127 Both cholesterol and bile acids stimulate the hydrolysis of ATP by ABCG5/8 in vitro. Presumably, these activities signify substrate‐ and acceptor‐level activation, respectively.…”

Section: Export Of Cholesterol By Abc Transportersmentioning

confidence: 99%

Active cholesterol 20 years on

Lange

Steck

2020

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This review considers the following hypotheses, some well‐supported and some speculative. Almost all of the sterol molecules in plasma membranes are associated with bilayer phospholipids in complexes of varied strength and stoichiometry. These complexes underlie many of the material properties of the bilayer. The small fraction of cholesterol molecules exceeding the binding capacity of the phospholipids is thermodynamically active and serves diverse functions. It circulates briskly among the cell membranes, particularly through contact sites linking the organelles. Active cholesterol provides the upstream feedback signal to multiple mechanisms governing plasma membrane homeostasis, pegging the sterol level to a threshold set by its phospholipids. Active cholesterol could also be the cargo for various inter‐organelle transporters and the form excreted from cells by reverse transport. Furthermore, it is integral to the function of caveolae; a mediator of Hedgehog regulation; and a ligand for the binding of cytolytic toxins to membranes. Active cholesterol modulates a variety of plasma membrane proteins—receptors, channels and transporters—at least in vitro.

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“…(G5-E146Q) and ABCG5WT/G8R543S (G8-R543S), two loss-of-function/sitosterolemia missense mutants [22,37], and ABCG5A540F/G8WT (G5-A540F), a loss-of-function mutant with putative sterol-binding defect [21] ( Figure 1B & Supplementary Figure 1). The purified mutants were preincubated with E.…”

Section: Missense Mutants Impair Chs-coupled Atpase Activity Of Abcg5mentioning

confidence: 99%

Transmembrane polar relay drives the allosteric regulation for ABCG5/G8 sterol transporter

Xavier

Zein

Venes

et al. 2020

Preprint

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The heterodimeric ATP-binding cassette (ABC) sterol transporter, ABCG5/G8, is responsible for the biliary and transintestinal secretion of cholesterol and dietary plant sterols. Missense mutations of ABCG5/G8 can cause sitosterolemia, a loss-of-function disorder characterized by plant sterol accumulation and premature atherosclerosis. A new molecular framework was recently established by a crystal structure of human ABCG5/G8 and reveals a network of polar and charged amino acids in the core of the transmembrane domains, namely polar relay. In this study, we utilize genetic variants to dissect the mechanistic role of this transmembrane polar relay in controlling ABCG5/G8 function. We demonstrated a sterol-coupled ATPase activity of ABCG5/G8 by cholesteryl hemisuccinate (CHS), a relatively water-soluble cholesterol memetic, and characterized CHS-coupled ATP catalysis by using three loss-of-function missense variants, two sitosterolemia mutations (E146Q and R543S; within polar relay) and one sterol-binding mutation (A540F; distant from the polar relay). The results established an in vitro phenotype of the loss-of-function and missense mutations of ABCG5/G8, showing significantly impaired ATPase activity and loss of energy sufficient to weaken the polar relay network by all three mutants. Our data herein provide a biochemical evidence underlying the importance of the polar relay in regulating the catalytic activity of ABCG5/G8 sterol transporter.

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ABCG5/G8: a structural view to pathophysiology of the hepatobiliary cholesterol secretion

Cited by 49 publications

References 80 publications

Vitamin D Status of Mice Deficient in Scavenger Receptor Class B Type 1, Cluster Determinant 36 and ATP-Binding Cassette Proteins G5/G8

Vitamin D Status of Mice Deficient in Scavenger Receptor Class B Type 1, Cluster Determinant 36 and ATP-Binding Cassette Proteins G5/G8

Active cholesterol 20 years on

Transmembrane polar relay drives the allosteric regulation for ABCG5/G8 sterol transporter

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