Disease relevance of ABCG8

• These results suggest that, in patients with hypercholesterolemia, the ABCG8 D19H variant is associated with greater LDLC-lowering response to atorvastatin therapy [1].
• The identification of defective structures in the ABCG5 or ABCG8 transporters in patients with the rare disease of sitosterolemia elucidated their role as sterol efflux pumps regulating at least in parts the intestinal sterol absorption and the hepatic sterol output [2].
• A female subject with each mutation was symptomatic with coronary atherosclerosis: a 5-year-old ABCG8 S107X homozygote and a 75-year-old ABCG5 exon 3 I/D homozygote; these represent the extreme ends of the spectrum of vascular involvement in sitosterolemia [3].
• Are plasma lipid levels related to ABCG5/ABCG8 polymorphisms? A preliminary study in siblings with gallstones [4].
• Image in cardiovascular medicine. Aortic xanthomatosis with coronary ostial occlusion in a child homozygous for a nonsense mutation in ABCG8 [5].

High impact information on ABCG8

• We identified seven different mutations in two adjacent, oppositely oriented genes that encode new members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family (six mutations in ABCG8 and one in ABCG5) in nine patients with sitosterolemia [6].
• Mutations in either ATP-binding cassette (ABC) G5 or ABCG8 cause sitosterolemia, an autosomal recessive disorder of sterol trafficking [7].
• The Endo H-sensitive forms of ABCG5 and ABCG8 were confined to the endoplasmic reticulum (ER), whereas the mature forms were present in non-ER fractions in cultured hepatocytes [7].
• Immunoelectron microscopy revealed ABCG5 and ABCG8 on the plasma membrane of these cells [7].
• Both ABCG5 and ABCG8 underwent N-linked glycosylation [7].

Biological context of ABCG8

• Mutations in either ABCG5 or ABCG8 result in an identical clinical phenotype, suggesting that these two half-transporters function as heterodimers [8].
• ABCG5 (G5) and ABCG8 (G8) are ATP-binding cassette (ABC) transporters that limit intestinal absorption and promote biliary excretion of neutral sterols [8].
• ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion [8].
• The ABCG5 and ABCG8 transporters, defective in beta-sitosterolemia, are also now considered interesting targets in the control and influence of total body sterol homeostasis [9].
• In this paper we describe three novel mutations causing sitosterolemia: 1) a frameshift mutation (c.336-337insA) in ABCG5 that results in premature termination of the protein at amino acid 197; 2) a missense mutation that changes a conserved residue c.1311C>G; N437K) in ABCG5 and 3) a splice site mutation in ABCG8 (IVS1-2A>G) [10].

Anatomical context of ABCG8

• Human gallbladder cDNA expressed message for ABCG5 and ABCG8 [11].
• ABCG5 and ABCG8 are expressed in gallbladder epithelial cells [11].
• GBEC therefore express ABCG5 and ABCG8; these sterol transporters may play a role in mediating AP cholesterol efflux in the gallbladder epithelium [11].
• Furthermore, adenosine triphosphate (ATP)-binding cassette (ABC) transporters ABCG5 and ABCG8 represent apical sterol export pumps that promote active efflux of cholesterol and plant sterols from enterocytes back into the intestinal lumen for excretion [12].
• The 2 adenosine triphosphate (ATP)-binding cassette (ABC) half-transporters ABCG5 and ABCG8 are expressed in the mucosa cells and the canalicular membrane, and they resecrete sterols, especially absorbed plant sterols, back into the intestinal lumen and from the liver into bile [13].

Associations of ABCG8 with chemical compounds

• Two ATP-binding cassette (ABC) transporters, ABCG5 and ABCG8, have been proposed to limit sterol absorption and to promote biliary sterol excretion in humans [14].
• Our results provide a new aspect of biochemical and functional characterization of the ABCG5/ABCG8 proteins and their possible involvement in steroid hormone transport or regulation [15].
• Upon high level expression of the ABCG5 and ABCG8 proteins in baculovirus-Sf9 cell expression system we found a distinct, vanadate sensitive ATPase activity in isolated membrane preparations only when the two proteins were co-expressed [15].
• Since biliary sitosterol secretion is preserved, although not elevated in the sitosterolemic mice, this observation suggests that mechanisms other than by Abcg8/sterolin-2 may be responsible for its secretion into bile [16].
• In summary, on the island of Kosrae, a strong founder effect of a mutant ABCG8 allele results in a large number of carriers with increased plasma plant sterol levels and decreased lathosterol levels [17].

Regulatory relationships of ABCG8

• In polarized WIF-B cells, recombinant ABCG5 localized to the apical (canalicular) membrane when coexpressed with ABCG8, but not when expressed alone [7].

Other interactions of ABCG8

• To test this hypothesis, a P1 clone containing the human ABCG5 and ABCG8 genes was used to generate transgenic mice [14].
• Mutating this LRH-1 binding site reduced promoter activity of the human ABCG5/ABCG8 intergenic region more than 7-fold in HepG2 and Caco2 cells [18].
• We conclude that the ABCG8 H19 and CYP7A1 C-204 alleles appear to interact in a dose-dependent manner on atorvastatin response [19].

Analytical, diagnostic and therapeutic context of ABCG8

• Hepatic ABCG5/ABCG8 expression, at least during the early phase after transplantation, is not directly related to biliary cholesterol secretion in humans [20].
• METHODS: Here we report the biochemical and immuno-localization of ABCG5 and ABCG8 in human liver, gallbladder and intestine using cell fractionation and immunohistochemical analyses [21].

References