Hepatic ABC Transporters
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Hepatic ABC Transporters
ABC (ATP-binding cassette) transporters are a large superfamily of integral membrane proteins involved in the cellular export or import of a wide variety of different substances, including ions, lipids, cyclic nucleotides, peptides, and proteins. ABC transporters are systemically classified into eight subfamilies by sequence similarity, i.e., ABCA (ABC1), ABCB (MDR/TAP), ABCC (MRP/CFTR), ABCD (ALD), ABCE (RNAseLI/OABP), ABCF (GCN20), ABCG (White) and ANSA subclass. In general, the transmembrane part of ABC transporters contains a polar channel formed by two homologous domains, each usually consisting of five (uptake transporters) or six (efflux transporters) transmembrane alpha-helices (Ref.1 & 2).

Typically, ABC proteins are relatively specific for a particular set of substrates (except ABCB1). Substrates can be amino acids, sugars, inorganic ions, peptides, proteins, lipids and various organic and inorganic compounds. Various family members are attractive candidates for Flippases that translocate lipids from the inner to the outer leaflet of the plasma membrane. The canalicular membrane in the hepatocytes contains several ATP-dependent export pumps: MDR1 (Multidrug-Resistance-1 P-Glycoprotein, also known as ABCB1), the phospholipid transporter MDR3 (ABCB4), the canalicular MRP2 (Multispecific-Organic-Anion Transporter or cMOAT), and the canalicular BSEP (Bile Salt Export Pump or SPGP). In addition, the canalicular membrane contains several ATP-independent transport systems, including ClCn (Chloride Channel), a chloride-bicarbonate AE2 (Anion Exchanger isoform-2) for secretion of bicarbonate, and a Gsh (Glutathione) transporter (Ref.3). The liver-specific ABC transporter MDR3 specifically transports phosphatidylcholine across the canalicular membrane during bile formation. By contrast, MDR1 expels a variety of short-chain lipids and amphiphilic drugs from the cell. It mediates outward transport of natural lipids such as PAF (Platelet-Activating Factor), phosphatidylserine, sphingomyelin and glucosylceramide. The glutathione-dependent multidrug transporter MRP1 (Multispecific Organic Anion Transporter), transport short-chain phosphatidylcholine, phosphatidylserine, sphingomyelin and GlcCer analogs, and helps to maintain the outward orientation of natural choline phospholipids in the plasma membrane (Ref.4). ABCA1 controls the extrusion of membrane phospholipids (mostly hosphatidylcholine) and cholesterol to cell surface-bound apolipoproteins. The ABCA1-dependent control on the lipid content of the membrane dramatically influences the plasticity and fluidity of the membrane itself and, as a result, affects the lateral mobility of membrane proteins and/or their association with membrane domains of special lipid composition.

There are two sinusoidal systems for bile-salt uptake in hepatocytes-NTCP (Sodium-Taurocholate Cotransporter) and a sodium-independent OATP (Organic Anion-Transporting Polypeptides). Sodium-dependent uptake of bile salts through the NTCP is driven by an inwardly directed sodium gradient generated by Na+/K+-ATPase and the membrane potential generated in part by a KCn (Potassium Channel). In addition, the basolateral membrane contains a Na+-H+ (Sodium-Hydrogen Exchanger) and a Na+-HCO3- (Sodium-Bicarbonate) symporter. In addition, Na+/K+-ATPase, together with a KCn, helps to generate a transmembrane electrical potential (Ref.5). These chemical and electrical potentials are used for the maintenance of intracellular ion and pH homeostasis. They provide the driving forces for proton extrusion by a mechanism of Na+-H+ exchange and for HCO3- entry, as well as for the electrogenic Na+-dependent uptake of conjugated bile salts (or bile acids). In contrast to conjugated bile salts, the unconjugated bile salt cholate, the organic anion sulfobromophthalein, and numerous other lipophilic albumin-bound compounds are transported from plasma into hepatocytes by Na+-independent transport systems, including the OATP.

ABC transporters are probably the most common as well as the most wide-spread active transport systems. They have been widely implicated in disease processes, such as Stargardt macular degeneration, cholestasis of pregnancy, cystic fibrosis, and confer resistance of bacterial and eukaryotic cells to antibiotics and numerous drugs applied for the treatment of infectious diseases, cancer, malaria, AIDS, etc (Ref.6 & 7).