ABC Transporters involved in Hepatobiliary Transport

The formation of bile is an elementary physiological function of the liver, which involves numerous transport proteins located in the basolateral (sinusoidal) and apical (canalicular) membranes of hepatocytes (Fig. 3.9). Bile, which is composed of bile salts, phospholipids, cholesterol, bilirubin and many other small molecules, is necessary for the micellar absorption of lipids from the intestine as well as for the excretion of endogenous and xenobiotic compounds [228]. The first step in hepatobiliary transport, the uptake of compounds into liver cells is mediated by proteins of the solute carrier (SLC) superfamily [229]. Among these, the Na+/taur-

Monovalent Bile Salts Ntcp

Fig. 3.9 Overview oflipid transport proteins in hepatocytes. Monovalent bile salts, such as taurocholate, are taken up into hepatocytes by the sodium-taurocholate co-transporting polypeptide (NTCP) [229]. The organic anion transporting polypeptides 1 and 2 (OATP1—2) are responsible for the charge-independent uptake of bulky organic compounds, including bile salts and other organic anions, uncharged cardiac glycosides, steroid hormones, and certain type 2 organic cations [230]. Small, type 1 organic cations are transported by the organic cation transporter OCT1. Several ABC proteins belonging to the ABCB (MDR) subfamily or ABCC (MRP) subfamily are expressed in liver [231]. ABCB1 (MDR1) is responsible for the excretion of bulky amphi-phatic compounds into bile, whereas ABCB4 (MDR3) is a phosphatidylcholine translocase. Monovalent bile salts are secreted into the bile canaliculi by the bile salt export pump BSEP (ABCB11). ABCC2 (MRP2) functions as a multispecific organic anion transport protein in the canalicular membrane. ABCC1 (MRP1), expressed at very low levels in the basolateral membrane in normal hepatocytes, has a similar substrate specificity to MRP2. ABCC3 (MRP3) preferentially translocates conjugates with glucuronate or sulfate, whereas the physiological substrates for ABCC6 (MRP6) are unknown.

ocholate co-transporting peptide (NTCP), located in the basolateral membrane is responsible for the uptake of the majority of bile salts in hepatocytes. Small (type I) organic ions (e.g. choline, drugs, and monoamine neurotransmitters) are transported by the organic cation transporter 1 (OCT1), whereas bulky (type II) organic cations, glutathione conjugates, and some amount of bile acids are taken up the organic anion-transporting polypeptide (OATP1) [230].

The subsequent step in hepatobiliary transport, the translocation of compounds from hepatocytes into the bile, involves ABC transporters localized in the hepato-cyte apical (canalicular) membrane [231]. These ABC proteins belong to the ABCB (MDR) and ABCC (MRP) subfamilies. Despite the low expression level of ABCB1

(MDR1) in normal human liver [232], data from Mdr1a/1b knockout mice, which are very sensitive to xenobiotics, neurotoxins, and chemotherapeutics, provide evidence that the major function of ABCB1 is the protection of hepatocytes against harmful substances by active translocation into the bile [233, 234]. It is now widely accepted that ABCB4 (MDR3), which is exclusively expressed in the liver apical membrane, is a bile canalicular phosphatidylcholine translocase (Fig. 3.9). This function has been confirmed by a series of experimental data: (1) mice with a target disruption of the Mdr2 gene, the mouse homolog of ABCB4 (MDR3), exhibit a complete absence of PC and strongly decreased levels of cholesterol from bile [194]; (2) transgenic expression of human MDR3 in these mice can fully restore PC secretion into the bile [235]; and (3) mutations in the human ABCB4 (MDR3) gene cause progressive familial intrahepatic cholestasis (PFIC) type 3 [10] (Tab. 3.2).

The third member of the ABCB subfamily involved in hepatobiliary secretion is ABCB11 (SPGP). Gerloff et al. [236] have shown that membrane vesicles isolated from ABCB11-overexpressing Sf9 cells display ATP-dependent taurocholate uptake characteristics similar to those of liver canalicular membrane vesicles, and thus concluded that ABCB11 is the major, if not the only bile salt transporter of mammalian liver, hence the name bile salt export pump (BSEP). Further support for this proposition comes from the findings that the ABCB11 (BSEP) gene is mutated in patients with progressive intrahepatic cholestasis type 3 (PFIC3) [11], a syndrome characterized by very low levels of biliary bile salts and elevated concentrations of serum bile salts.

In the ABCC (MRP) subfamily, at least four members have been shown to be expressed in liver cells [95]. In hepatocytes and other polarized epithelial cells, ABCC2 (MRP2) is localized and is highly expressed at the canalicular membrane. In contrast, ABCC1 (MRP1) present at the basolateral membrane domain, is expressed very low in normal liver. As listed in Tab. 3.1 and displayed in Fig. 3.9, physiological substrates for ABCC1 and ABCC2 comprise glutathione conjugates (e.g. leukotriene C4), estrogen- and bilirubin-glucuronides, taurolithocholate 3-sul-fate, and glutathione disulfide (GSSG). However, due to the differences in the overall expression levels and because of greatly different transport kinetics, ABCC2 seems to be the major transporter of anionic conjugates.

Likewise, hereditary defects of ABCC2 in humans cause the Dubin-Johnson syndrome, which is associated with defects in biliary secretion of amphiphilic an-ionic conjugates including bilirubin-glucuronides [237, 238]. Glucuronate- and sul-fate-conjugates are also substrates for ABCC3 (MRP3), which has been localized to the basolateral membrane of hepatocytes [239]; however, in contrast to ABCC1 and ABCC2, glutathione conjugates are poor substrates for ABCC3.

ABCC6 (MRP6), which has been localized to the lateral hepatocyte membrane [240], is capable of transporting the anionic cyclopentapeptide BQ123, an endothe-lin receptor antagonist; however, the physiological substrate for ABCC6 has not been elucidated so far.

Lower Your Cholesterol In Just 33 Days

Lower Your Cholesterol In Just 33 Days

Discover secrets, myths, truths, lies and strategies for dealing effectively with cholesterol, now and forever! Uncover techniques, remedies and alternative for lowering your cholesterol quickly and significantly in just ONE MONTH! Find insights into the screenings, meanings and numbers involved in lowering cholesterol and the implications, consideration it has for your lifestyle and future!

Get My Free Ebook

Post a comment