Sterolins-ABCG5 and ABCG8
Proteins

Author: Massimiliano Boero
Date: 16/02/2014

Description

DEFINITION

Sterolins-1 and 2 are ATP-binding cassette (ABC) transporters, members 5 and 8 of the ABCG group (ABCG5 and ABCG8).

ABC transporters utilize the energy derived from ATP binding/ hydrolysis to drive substrate translocation across the membrane.
ABC transporters are fundamental to membrane transport of a wide variety of substrates including amino acids, lipids, lipopolysaccharides, inorganic ions, peptides, sugars, metal ions, drugs and proteins.

The G subfamily of ABC transporters consists of half-transporters, which oligomerise to form the functional transporter.

They are responsible, with other proteins, for sterol exchange.

from Cholesterol Serum Influx/Efflux

THE GENE

The discovery of ABCG5 and ABCG8 came when the sitosterolaemia locus on chromosome 2p21 (STSL) was localized in 1998.
ABCG5 and G8 genes have 13 exons and twelve introns.
Mapping a gene involved in regulating dietary cholesterol absorption. The sitosterolemia locus is found at chromosome 2p21, 1998
Sterolins are transcribed in opposite directions with a small, shared intergenic region of 374 bp , which means that regulation of both genes’ transcription is most likely mediated by common mechanisms.
Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters, 2000

About polymorphisms of the genes, some are unique of a specific population. For example, no detection of SNP ABCG8 M429V allele of Japanese population was recorded in either the Caucasian or the African- American population studied.
This variability might have effects on generalization regarding the effect of one specific polymorphism on cholesterol metabolism.
A detailed Hapmap of the Sitosterolemia locus spanning 69 kb; differences between Caucasians and African-Americans, 2006
Polymorphisms in ABCG5/G8 transporters linked to hypercholesterolemia and gallstone disease, 2008

Sterolins’ genes are mammalian homologues of the Drosophila White gene, which plays an essential role in the cellular uptake of precursors of the eye pigments.
Cloning of the cDNA for a human homologue of the Drosophila white gene and mapping to chromosome 21q22.3, 1996

DatabaseLink
WikigenesABCG5
WikigenesABCG8
GeneCardsABCG5
GeneCardsABCG8
Your Favorite Gene SigmaABCG5
Your Favorite Gene SigmaABCG8

CHEMICAL STRUCTURE

The ABCG5 and ABCG8 proteins unite to form the functional heterodimeric transporter.
ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion, 2003

The 3D structure of ABCG proteins remains unknown, with data restricted to electron microscopy studies of human ABCG2.
Purification and 3D structural analysis of oligomeric human multidrug transporter ABCG2, 2006
The ABCG family of membrane-associated transporters: you don’t have to be big to be mighty, 2011

SYNTHESIS AND TURNOVER

The molecular mechanisms of synthesis and turnover remain largely unexplored; we just know few probable molecules involved in the regulation (see below).
Cholesterol and non-cholesterol sterol transporters:ABCG5, ABCG8 and NPC1L1: a review, 2008
The ABCG family of membrane-associated transporters: you don’t have to be big to be mighty, 2011

There is some evidence for a post-translational level of regulation:

CELLULAR FUNCTIONS

  • cellular localization

ABCG5/G8 are exclusively expressed throughout the gastro-intestinal tract, liver and gall bladder. Expression is highest in the small intestine and liver with lower expression levels in the large intestine.
Localization of ABCG5 and ABCG8 proteins in human liver, gall bladder and intestine, 2004

  • biological function

Excretion of cholesterol and plant sterol from liver and gut.

Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol, 2002

Biliary cholesterol concentrations in transgenic mice were five to seven-fold higher, compared with wild-type.

How?

One hypothesis argues that ABCG5/ABCG8 may act as ‘extruders’, exposing sterols in the outer leaflet of the membrane for facilitated extraction into the lumen by such sterol acceptors, such as bile acid phospholipid complexes.
Role of ABC transporters in secretion of cholesterol from liver into bile, 2003

Other researchers have proposed that sterolins may act as ‘flippases’, akin to the flipping of phospholipids from the inner to the outer leaflet of the apical membranes.
Biliary cholesterol secretion by the twinned sterol half-transporters ABCG5 and ABCG8, 2002

From KEGG

REGULATION: FEW HIGHLIGHTS

ABCG5/G8 expression is regulated by the nuclear orphan receptor liver receptor homologue-1 (LXR), which has his effect when cholesterol intake increases.
The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter, 2004

ATPase activity of these heterodimers has also been shown to be stimulated by androstenedione and inhibited by progesterone, although the significance of this remains to be determined.
Co-expression of human ABCG5 and ABCG8 in insect cells generates an androstan stimulated membrane ATPase activity, 2006

PATHOLOGICAL RELEVANCE

Mutations in either ABCG5 or ABCG8 cause sitosterolaemia, a rare autosomal recessive disorder characterised by accumulation of both plant-derived sterols and animal cholesterol in plasma and tissues, leading to the development of xanthomas and other disorders.

OTHER MULTIFACTORIAL DISEASES INVOLVED:

Over-expression of ABCG5/ABCG8 in hypercholesterolemic mice caused a significant reduction in plasma cholesterol and atherosclerotic lesions compared to control mice.
High-level expression of ABCG5 and ABCG8 attenuates diet-induced hypercholesterolemia and atherosclerosis in Ldlr _/ _ mice, 2004

In patients with hypercholesterolemia, the ABCG8 rs11887534 (D19H) variant shows an association with higher risk of coronary heart disease. Other variants did not.
ABCG5/ABCG8 in cholesterol excretion and atherosclerosis, 2014

The presence of mutated polymorphisms of ABCG8 (D19H and T400K) was associated with cholesterol gallstones.
The mutated allele might confer a more efficient transport of cholesterol into bile, thus causing lower plasma cholesterol, cholesterol hypersaturation in bile and promoting the formation of cholesterol gallstones.
Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol, 2007
A genome-wide association scan identifies the hepatic cholesterol transporterABCG8 as a susceptibility factor for human gallstone disease, 2007

Statin : treatment for hypercholesterolemia or risk factor for gallstone disease?

Carriers of the ABCG8 D19H and C1199A mutant allele had a greater plasma LDL-C reduction after treatment with atorvastatin..
Interactions between common genetic polymorphisms in ABCG5/G8 and CYP7A1 on LDL cholesterol-lowering response to atorvastatin, 2004
Interactions between CYP7A1 A-204C and ABCG8 C1199A polymorphisms on lipid lowering with atorvastatin, 2011

Controversial perspectives: statin and gallstone

Hepatic secretion of cholesterol and ABCG5/G8 expression are strongly stimulated by thyroid hormone in hypophysectomized(Hx) rats. Also the intestinal uptake of cholesterol is influenced by TH.
Dramatically increased intestinal absorption of cholesterol following hypophysectomy is normalized by thyroid hormone, 2008

TH-induced stimulation of biliary cholesterol secretion is mediated by the ABCG5/G8 complex.
Stimulation of Murine Biliary Cholesterol Secretion by Thyroid Hormone is Dependent on a Functional ABCG5/G8 Complex, 2012
TH enhances hepatic activity, not only cholesterol secretion.

Attachments
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11484_ch_fosfo_ba_T3.gifmassimiliano.boero16/02/2014
11485_drammatic_secr_T4.gifmassimiliano.boero16/02/2014
11489_plasma_chol_overexpr.gifmassimiliano.boero16/02/2014
11494_sexual_hormones.gifmassimiliano.boero16/02/2014
11519_Yu_2002_mice_knockout.gifmassimiliano.boero16/02/2014
11522_flippase.gifmassimiliano.boero16/02/2014
11527_1teorprand.gifmassimiliano.boero16/02/2014
11528_1teorinterprand.gifmassimiliano.boero16/02/2014
11538_sterol_traffick.gifmassimiliano.boero16/02/2014
11547_G5liver.gifmassimiliano.boero16/02/2014
11548_gallbladder.gifmassimiliano.boero16/02/2014
11549_intestine.gifmassimiliano.boero16/02/2014
11553_AA.gifmassimiliano.boero16/02/2014
11556_AA.gifmassimiliano.boero16/02/2014
11557_chol_abs.gifmassimiliano.boero16/02/2014
11558_chol_secr.gifmassimiliano.boero16/02/2014
11560_AA.gifmassimiliano.boero16/02/2014
11561_chol_abs.gifmassimiliano.boero16/02/2014
11562_chol_secr.gifmassimiliano.boero16/02/2014
11563_in_membr.gifmassimiliano.boero16/02/2014
11566_intron_seq.gifmassimiliano.boero16/02/2014
11568_intron_seq.gifmassimiliano.boero16/02/2014
11569_G_subtypes_localiz.gifmassimiliano.boero16/02/2014
11571_intron_seq.gifmassimiliano.boero16/02/2014
11572_G_subtypes_localiz.gifmassimiliano.boero16/02/2014
11573_2011table_Gsubtipes.gifmassimiliano.boero16/02/2014
2011table_Gsubtipes.gifmassimiliano.boero16/02/2014
3D_ABCG2.gifmassimiliano.boero16/02/2014
AA.gifmassimiliano.boero16/02/2014
G_subtypes_localiz.gifmassimiliano.boero16/02/2014
Regulation.gifmassimiliano.boero19/02/2014
chol_abs.gifmassimiliano.boero16/02/2014
chol_secr.gifmassimiliano.boero16/02/2014
g5_8_mut_polymo.gifmassimiliano.boero16/02/2014
in_membr.gifmassimiliano.boero16/02/2014
intron_seq.gifmassimiliano.boero16/02/2014
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