what are the role of O.S.T
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Abstract
The organic solute and steroid transporter, Ost alpha-Ost beta, is an unusual heteromeric carrier that appears to play a central role in the transport of bile acids, conjugated steroids, and structurally-related molecules across the basolateral membrane of many epithelial cells. The transporter’s substrate specificity, transport mechanism, tissue distribution, subcellular localization, transcriptional regulation, as well as the phenotype of the recently characterized Ost alpha-deficient mice all strongly support this model. Ost alpha-Ost beta is composed of a predicted 340-amino acid, 7-transmembrane (TM) domain protein (Ost alpha) and a putative 128-amino acid, single-TM domain polypeptide (Ost beta). Heterodimerization of the two subunits increases the stability of the individual proteins, facilitates their post-translational modifications, and is required for delivery of the functional transport complex to the plasma membrane. Ost alpha and Ost beta are expressed in nearly all human tissues that have been examined, but are most abundant in the small intestine, kidney, liver, testis, adrenal gland and other steroidogenic tissues. Ost alpha-Ost beta substrates include bile acids, steroids (estrone 3-sulfate, dehydroepiandrosterone 3-sulfate, and digoxin), and prostaglandin E2, indicating a role of Ost alpha-Ost beta in the disposition of key cellular metabolites and signaling molecules. Transport occurs by a facilitated diffusion mechanism, and thus Ost alpha-Ost beta can mediate cellular efflux or uptake depending on that substrate’s electrochemical gradient. Additional strong evidence for a role of Ost alpha-Ost beta in sterol homeostasis was provided by recent studies in Ost alpha-deficient mice. These mice display a marked defect in intestinal bile acid and conjugated steroid absorption; a decrease in bile acid pool size and serum bile acid levels; altered intestinal, hepatic and renal disposition of known substrates of the transporter; and altered serum triglyceride, cholesterol, and glucose levels. Taken together, these observations indicate that Ost alpha-Ost beta is essential for bile acid and sterol disposition, and suggest that the carrier may be involved in human conditions related to imbalances in bile acid or lipid homeostasis.
Keywords: Conjugated steroids, bile acid transport, FXR, Ost alpha-Ost beta, Ost alpha−/− mice
2. Introduction
The steroid-derived class of compounds, including the bile acids, steroid hormones, and other cholesterol metabolites, play critical roles in human physiology; however, relatively little is known about the transport proteins that mediate cellular import and export of these molecules. Although it is often assumed that transport of steroid hormones occurs by simple diffusion, this mode of transport would largely preclude the ability to regulate intracellular concentrations of these important bioactive and signaling molecules, and is therefore unlikely to play a significant role in their disposition. The present report summarizes the evidence for an important role of the organic solute and steroid transporter, Ost alpha-Ost beta, in the disposition of sterols, and focuses on the contribution of Ost alpha-Ost beta to the enterohepatic circulation of bile acids.
3. Bile acid synthesis and disposition
Bile acids are the major products of cholesterol catabolism, and they regulate a multitude of biological processes, including hepatic bile secretion and the intestinal absorption of fat and fat-soluble vitamins (1–3). Bile acids also modulate triglyceride, cholesterol, energy, and glucose homeostasis through their activation of specific receptors and signaling pathways (4).
The liver is the only organ that synthesizes bile acids. Approximately 5–10% of the bile acids made in the liver originate from peripherally obtained precursors and around 90–95% directly from cholesterol within hepatocytes (5). Specific hepatic enzymes oxidize cholesterol, and these initial oxidized products are further metabolized to bile acids, which are then secreted into bile and delivered into the intestine (6). Bile acids are defined as primary bile acids when they are sythesized in liver, or as secondary bile acids when they are made by bacteria in the intestine. The classical or neutral pathway and the acidic pathway are responsible for the production of at least 95% of the bile acids, and these two pathways contribute about equally to bile acid synthesis in humans (5).
The organic solute and steroid transporter, Ost alpha-Ost beta, is an unusual heteromeric carrier that appears to play a central role in the transport of bile acids, conjugated steroids, and structurally-related molecules across the basolateral membrane of many epithelial cells. The transporter’s substrate specificity, transport mechanism, tissue distribution, subcellular localization, transcriptional regulation, as well as the phenotype of the recently characterized Ost alpha-deficient mice all strongly support this model. Ost alpha-Ost beta is composed of a predicted 340-amino acid, 7-transmembrane (TM) domain protein (Ost alpha) and a putative 128-amino acid, single-TM domain polypeptide (Ost beta). Heterodimerization of the two subunits increases the stability of the individual proteins, facilitates their post-translational modifications, and is required for delivery of the functional transport complex to the plasma membrane. Ost alpha and Ost beta are expressed in nearly all human tissues that have been examined, but are most abundant in the small intestine, kidney, liver, testis, adrenal gland and other steroidogenic tissues. Ost alpha-Ost beta substrates include bile acids, steroids (estrone 3-sulfate, dehydroepiandrosterone 3-sulfate, and digoxin), and prostaglandin E2, indicating a role of Ost alpha-Ost beta in the disposition of key cellular metabolites and signaling molecules. Transport occurs by a facilitated diffusion mechanism, and thus Ost alpha-Ost beta can mediate cellular efflux or uptake depending on that substrate’s electrochemical gradient. Additional strong evidence for a role of Ost alpha-Ost beta in sterol homeostasis was provided by recent studies in Ost alpha-deficient mice. These mice display a marked defect in intestinal bile acid and conjugated steroid absorption; a decrease in bile acid pool size and serum bile acid levels; altered intestinal, hepatic and renal disposition of known substrates of the transporter; and altered serum triglyceride, cholesterol, and glucose levels. Taken together, these observations indicate that Ost alpha-Ost beta is essential for bile acid and sterol disposition, and suggest that the carrier may be involved in human conditions related to imbalances in bile acid or lipid homeostasis.
Keywords: Conjugated steroids, bile acid transport, FXR, Ost alpha-Ost beta, Ost alpha−/− mice
2. Introduction
The steroid-derived class of compounds, including the bile acids, steroid hormones, and other cholesterol metabolites, play critical roles in human physiology; however, relatively little is known about the transport proteins that mediate cellular import and export of these molecules. Although it is often assumed that transport of steroid hormones occurs by simple diffusion, this mode of transport would largely preclude the ability to regulate intracellular concentrations of these important bioactive and signaling molecules, and is therefore unlikely to play a significant role in their disposition. The present report summarizes the evidence for an important role of the organic solute and steroid transporter, Ost alpha-Ost beta, in the disposition of sterols, and focuses on the contribution of Ost alpha-Ost beta to the enterohepatic circulation of bile acids.
3. Bile acid synthesis and disposition
Bile acids are the major products of cholesterol catabolism, and they regulate a multitude of biological processes, including hepatic bile secretion and the intestinal absorption of fat and fat-soluble vitamins (1–3). Bile acids also modulate triglyceride, cholesterol, energy, and glucose homeostasis through their activation of specific receptors and signaling pathways (4).
The liver is the only organ that synthesizes bile acids. Approximately 5–10% of the bile acids made in the liver originate from peripherally obtained precursors and around 90–95% directly from cholesterol within hepatocytes (5). Specific hepatic enzymes oxidize cholesterol, and these initial oxidized products are further metabolized to bile acids, which are then secreted into bile and delivered into the intestine (6). Bile acids are defined as primary bile acids when they are sythesized in liver, or as secondary bile acids when they are made by bacteria in the intestine. The classical or neutral pathway and the acidic pathway are responsible for the production of at least 95% of the bile acids, and these two pathways contribute about equally to bile acid synthesis in humans (5).
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