ABCG5 and ABCG8
Encyclopedia
ABCG5
and ABCG8
genes encode for two proteins sterolin-1 and -2, respectively. Sterolin-1 and –2 are two ‘half’ adenosine triphosphate binding (ATP
) cassette (ABC) transporters which found to be indispensable for the regulation of sterol absorption and excretion. Mutations in either genes
result in a lipid disorder, sitosterolemia
.
secretion into bile
.
In 1998, sitosterolemia (STSL) locus has been mapped to the short arm of human chromosome 2 (2p21) after studying 10 well-characterized families with this disorder. Subsequently, the STSL locus has been further localized to a less than 2 centimorgans (cM) region.
In 2001, The STSL locus was found to be comprises two genes, ABCG5 and ABCG8, encoding 2 members of the ABC-transporter family, named sterolin-1 and sterolin-2, respectively. , Sterolin-2, discovered after sterolin-1, is located <400 base pair (bp) upstream of sterolin-1 in the opposite orientation.
into bile, almost unchanged.
Sterolins are likely involved both in the selective transport of dietary cholesterol in and out of enterocytes and in selective sterol excretion by the liver into bile, as evidenced by the consequences when it is deficient or over expressed. The exact mechanism(s) whereby ABCG5/ABCG8 exert their effects on sterol metabolism has not yet been clarified. But it is suggested that the ABCG5/ABCG8 heterodimer shuttles cholesterol from the inner leaflet of the canalicular membrane through a chamber formed by the two half-transporters. Following ATP binding and hydrolysis, the complex undergoes a conformational change, flipping a cholesterol molecule into the outer membrane leaflet in a configuration that favors its release into the canalicular space.
Based on the clinical defects in sitosterolemia, ABCG5/ABCG8 are expressed in the liver and/or the intestine
. 5 These genes respond to environmental dietary sterols, although whether they are also increased by high phytosterols has yet to determined.
It is worth to mention that other gene products play a role in dietary-cholesterol transport (such as ABCA1).
ABCG5
ATP-binding cassette sub-family G member 5 is a protein that in humans is encoded by the ABCG5 gene.- Function :The protein encoded by this gene is a member of the superfamily of ATP-binding cassette transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes...
and ABCG8
ABCG8
ATP-binding cassette sub-family G member 8 is a protein that in humans is encoded by the ABCG8 gene.- External links :...
genes encode for two proteins sterolin-1 and -2, respectively. Sterolin-1 and –2 are two ‘half’ adenosine triphosphate binding (ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
) cassette (ABC) transporters which found to be indispensable for the regulation of sterol absorption and excretion. Mutations in either genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
result in a lipid disorder, sitosterolemia
Sitosterolemia
Sitosterolemia is a rare autosomal recessively inherited lipid metabolic disorder. It is characterized by hyperabsorption and decreased biliary excretion of dietary sterols leading to hypercholesterolemia, tendon and tuberous xanthomas, premature development of atherosclerosis, and abnormal...
.
Locus of the Genes
The molecular mechanisms regulating the absorption of dietary sterols in the body are poorly understood, and as sitosterolemia is a rare autosomal recessively inherited lipid metabolic disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols, studies have focused on the molecular basis of sitosterolemia to shed light on important principles concerning intestinal sterol absorption as well as cholesterolCholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
secretion into bile
Bile
Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...
.
In 1998, sitosterolemia (STSL) locus has been mapped to the short arm of human chromosome 2 (2p21) after studying 10 well-characterized families with this disorder. Subsequently, the STSL locus has been further localized to a less than 2 centimorgans (cM) region.
In 2001, The STSL locus was found to be comprises two genes, ABCG5 and ABCG8, encoding 2 members of the ABC-transporter family, named sterolin-1 and sterolin-2, respectively. , Sterolin-2, discovered after sterolin-1, is located <400 base pair (bp) upstream of sterolin-1 in the opposite orientation.
Structure of the Encoded Proteins
Typical ABC transporter consists of two transmembrane domains and two nucleotide-binding domains. However, the ABCG or White subfamily with its five fully characterized human members consists of half-size ABC proteins which probably dimerize to form active membrane transporters. In our case, it is suggested that ABCG5 and ABCG8 form a heterodimer . Among the half-size molecules, ABCG proteins have a peculiar domain organization characterized by a nucleotide-binding domain at the N-terminus followed by six transmembrane-spanning domains.Function
Under normal circumstances, a western diet contains almost equal amounts of cholesterol and noncholesterol sterols(such as plant sterols sitosterol, campesterol,and brassicasterol). However, only about 55% of total dietary cholesterol is absorbed and retained while almost none of the noncholesterol sterols are retained since the small amount of dietary non-cholesterols that do enter the body are rapidly excreted by the liverLiver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
into bile, almost unchanged.
Sterolins are likely involved both in the selective transport of dietary cholesterol in and out of enterocytes and in selective sterol excretion by the liver into bile, as evidenced by the consequences when it is deficient or over expressed. The exact mechanism(s) whereby ABCG5/ABCG8 exert their effects on sterol metabolism has not yet been clarified. But it is suggested that the ABCG5/ABCG8 heterodimer shuttles cholesterol from the inner leaflet of the canalicular membrane through a chamber formed by the two half-transporters. Following ATP binding and hydrolysis, the complex undergoes a conformational change, flipping a cholesterol molecule into the outer membrane leaflet in a configuration that favors its release into the canalicular space.
Based on the clinical defects in sitosterolemia, ABCG5/ABCG8 are expressed in the liver and/or the intestine
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
. 5 These genes respond to environmental dietary sterols, although whether they are also increased by high phytosterols has yet to determined.
It is worth to mention that other gene products play a role in dietary-cholesterol transport (such as ABCA1).