ABCG and ABCA Regulation of Sterol Metabolism
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ABCG and ABCA Regulation of Sterol Metabolism

ABC (ATP Binding Cassette Transporters) comprise a large family of membrane-spanning proteins that are responsible for transporting a variety of substrates in prokaryotes and eukaryotes. The most intriguing and, arguably, the most important membrane proteins for this purpose are the ABC. These proteins, found in all species, use the energy of ATP hydrolysis to translocate specific substrates across cellular membranes. Many of these transporters are responsible for the translocation of lipophilic substrates such as phospholipids, bile acids, and sterols (Ref.1 & 2).

Sterols in a normal Western diet usually consist of cholesterol (250-500 mg) and noncholesterol sterols (200-400 mg), mainly plant sterols such as sitosterol and also sterols from fish. Dietary sterols including cholesterol and plant sterols, which enter the intestinal epithelial cells via micellar transport, are released along the lysosomal route. Beta-Sitosterol and other plant sterols are directly transported back to the gut lumen by the heterodimeric ABCG5-ABCG8 complex by means of a sort of kickback mechanism, which may also efflux cholesterol, thereby regulating total sterol absorption. The retained sterols are routed along the ACAT1 (Acyl CoA: Cholesterol Acyltransferase) and ACAT2 pathway in the ER (Endoplasmic Reticulum) and either stored as CE (Cholesteryl Esters) in lipid droplets or alternatively packed into chylomicrons for further transport back to the liver. The sterols are either transported to peripheral tissues by VLDL (Very Low Density Lipoproteins) and LDL (Low Density Lipoproteins) particles or converted to bile acids. Also, a direct track into the bile duct for excretion exists mediated by ABCG5 and ABCG8. In addition to ABCG5 and ABCG8, other ABC transporters including ABCG1 and ABCA1 also participate in intestinal sterol absorption mechanisms (Ref.3). ABCA1, which resides in the plasma membrane, is targeted via AP2 (Adaptor Protein-2)-COP (Coatomer Protein) controlled mechanisms, whereas ABCG1 is routed to the trans-Golgi network compartment, presumably by dileucine-based AP3 (Adaptor Protein 3)-mediated vesicular transport. ABCG1 may function either as a homodimer or together with a second half-size transporter to translocate lipids to the plasma membrane, where ABCA1 facilitates further efflux from specialized membrane microdomains. ABCA1 targets cholesterol or UC (Unesterified Cholesterol) that enters the cells by the endosomal/lysosomal degradation pathway. This same source of cholesterol feeds into intracellular compartments that are the preferred substrate for the esterifying enzyme, ACAT. Thus ABCA1 removes cholesterol that would otherwise accumulate as intracellular CE or TG (Triglycerides) in the lipid droplets. Two mechanisms have been proposed to account for this targeting. Excess intracellular cholesterol or might be packaged into transport vesicles or rafts, in the Golgi apparatus, which translocate to sites in the plasma membrane containing ABCA1. Alternatively, ABCA1 and ApoA-I-containing vesicles travel to intracellular lipid deposits, where ABCA1 pumps lipids into the vesicle lumen for release by exocytosis. ABCA1 recycles rapidly between the plasma membrane and late endosomal-lysosomal compartments, consistent with this second mechanism. This rapid recycling however functions to regulate ABCA1 synthesis and degradation rather than lipid transport (Ref.4). DGAT1 and DGAT2 (Diacylglycerol Acyltransferase) catalyzes the final committed step in TG synthesis by using MAG (Monoacylglyceride) DAG (Diacylglycerol), MTP (Microsomal Transfer Protein) and FA-CoA (Fatty Acyl CoA) as its substrates. In addition to cholesterol and phospholipids, ABCA1 promotes secretion of Alpha-Tocopherol, ApoE (Apolipoprotein-E), ApoB (Apolipoprotein-B), and IL-1Beta (Interleukin-1Beta). ABCA1 can also promote phospholipid efflux from cells even when membranes are depleted of cholesterol, consistent with phospholipids being the primary substrate for ABCA1 (Ref.2).

ABC transporters are probably the most common as well as the most wide-spread active transport systems. Mutations in the genes encoding many of the ABC transporters of human cells are associated with diseases such as cystic fibrosis, adrenoleukodystrophy, Tangier disease, and obstetric cholestasis. Overexpression of certain ABC transporters is the most frequent cause of resistance to cytotoxic agents including antibiotics, antifungals, herbicides, and anticancer drugs. Mutations in ABCG5 or ABCG8 result in sitosterolemia. Patients with sitosterolemia have elevated levels of cholesterol and plant sterols, especially sitosterol, in both blood and tissues, and show evidence of premature coronary atherosclerosis. These increased levels result from hyper absorption of sterols (cholesterol and plant sterols) and a defect in the excretion of plant sterols from the liver into bile (Ref.5 & 6).