Disease relevance of ABCG5

• 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 [1].
• 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 [2].
• Are plasma lipid levels related to ABCG5/ABCG8 polymorphisms? A preliminary study in siblings with gallstones [3].
• Since these rat strains are also know to carry mutations at other genetic loci and the extent of phytosterolemia is only moderate, it is important to verify that the mutations in Abcg5 are causative for phytosterolemia and whether they contribute to hypertension [4].
• Flow cytometric analysis of the Th1-Th2 balance in healthy individuals and patients infected with the human immunodeficiency virus (HIV) receiving a plant sterol/sterolin mixture [5].

High impact information on ABCG5

• 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].
• Both ABCG5 and ABCG8 underwent N-linked glycosylation [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].
• Levels of hepatic ABCG5, ABCG8, and MDR3 messenger RNA (mRNA) were strongly correlated [8].
• In various (genetically modified) murine models, a strong relationship was found between hepatic expression of ABCG5/ABCG8 and biliary cholesterol content [8].

Biological context of ABCG5

• Mutations in either ABCG5 or ABCG8 result in an identical clinical phenotype, suggesting that these two half-transporters function as heterodimers [9].
• To test the hypothesis that genetic variation in ABCG5/8 might influence the plasma lipid response to statin therapy, we examined five nonsynonymous polymorphisms at the ABCG5/8 loci (Q604E, D19H, Y54C, T400K, and A632V) in 338 hypercholesterolemic patients treated with 10 mg atorvastatin [10].
• 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 [11].
• 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 [12].
• ABCG5 maps to human chromosome 2p21, between the markers D2S117 and D2S119 [13].

Anatomical context of ABCG5

• Human gallbladder cDNA expressed message for ABCG5 and ABCG8 [14].
• ABCG5 and ABCG8 are expressed in gallbladder epithelial cells [14].
• GBEC therefore express ABCG5 and ABCG8; these sterol transporters may play a role in mediating AP cholesterol efflux in the gallbladder epithelium [14].
• Immunoelectron microscopy revealed ABCG5 and ABCG8 on the plasma membrane of these cells [7].
• 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 [15].

Associations of ABCG5 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 [16].
• Expression of ABCG5 and ABCG8 is required for regulation of biliary cholesterol secretion [17].
• Finally, deoxycholic acid repressed the ABCG5 and ABCG8 promoters, consistent with bile acid regulation via the farnesoid X receptor-small heterodimeric partner-LRH-1 pathway [12].
• 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 [18].
• 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 [18].

Regulatory relationships of ABCG5

• The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter [12].
• 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 ABCG5

• To test this hypothesis, a P1 clone containing the human ABCG5 and ABCG8 genes was used to generate transgenic mice [16].
• Two other ABCG transporters, ABCG5 and ABCG8, mutations of which cause sitosterolemia, have been identified [19].
• Expression of ABCG5 and ABCG8 mRNA was lower in the diabetic patients (p<0.05) and MTTP expression was increased (p<0.05) [20].
• Interactions between common genetic polymorphisms in ABCG5/G8 and CYP7A1 on LDL cholesterol-lowering response to atorvastatin [21].
• These results indicate that the common polymorphisms of the ABCG5 and ABCA12 genes investigated here are not associated with AD [22].

Analytical, diagnostic and therapeutic context of ABCG5

• Hepatic ABCG5/ABCG8 expression, at least during the early phase after transplantation, is not directly related to biliary cholesterol secretion in humans [8].
• Furthermore, ABCG5/G8 eluted as a dimer on gel filtration columns [23].
• A conserved GATA site in the intergenic region was shown by site-directed mutagenesis to act as a repressor for the ABCG5 promoter [24].
• Sequence analysis revealed a novel Gln22X nonsense mutation in exon 1 or ABCG5 [25].
• 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 [26].

References