Mechanisms of Bile Secretion and Hepatic Transport

Boyer, James L.

doi:10.1007/978-1-4684-5404-8_12

Cited by 11 publications

(14 citation statements)

References 237 publications

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“…The lminal accumulation of such osmotically active solutes promotes the movement of water and electrolytes through tight junctions and across the canalicular membrane. The active secretion of bile acids and their conjugates has been shown to account for 40-50% of canalicular bile flow in all species examined (28). In this study, we demonstrated that expression of Mrp2 was significantly up-regulated in fibrate-treated mice.…”

Section: Discussionsupporting

confidence: 52%

A Nuclear Receptor-mediated Choleretic Action of Fibrates is Associated with Enhanced Canalicular Membrane Fluidity and Transporter Activity Mediating Bile Acid-independent Bile Secretion

Nishioka

Hyogo

Numata

et al. 2005

JAT

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Fibrates are commonly used lipid-lowering agents that act via PPARα α α α α, a member of the nuclear hormone receptor superfamily. The mechanism(s) of fibrate-induced changes in the hepatic canalicular membrane and bile lipids are still unknown. Therefore, the aim of this study was to investigate the influence of fibrates on hepatic lipid metabolism and to assess the hepatocellular cytoprotective effect on hepatocyte canalicular membrane. Male ICR mice were fed standard chow with or without bezafibrate (100 mg/kg) for 6 days. The expression of canalicular membrane transporters (Mdr2 and Mrp2) was evaluated by RT-PCR and Western blotting. Canalicular membrane fluidity was also investigated. Canalicular membrane fluidity was markedly increased by fibrates. The expression of mdr 2 and mrp2 mRNA and protein showed a significant increase in fibrate-treated mice. These results suggested that fibrates improve liver function by enhancing bile secretion. The mechanism of the choleretic action of fibrate therapy might involve the enhancement of bile acid-independent bile secretion, since increased expression of Mdr2 and Mrp2 was found in fibrate-treated animals. These changes were very likely mediated by PPARα α α α α, and the increase of canalicular membrane fluidity may have been partly associated with enhancement of this transporter activity. J Atheroscler Thromb, 2005; 12: 211-217.

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Section: Discussionsupporting

confidence: 52%

A Nuclear Receptor-mediated Choleretic Action of Fibrates is Associated with Enhanced Canalicular Membrane Fluidity and Transporter Activity Mediating Bile Acid-independent Bile Secretion

Nishioka

Hyogo

Numata

et al. 2005

JAT

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“…Our experimental findings delineate, for the first time, why biliary HCO À 3 secretion in man by far exceeds that in rodents 8 : Protonation of glycine-conjugated bile salts with a pK a !4,predominantly found in the human bile salt pool, 11 but not of taurine-conjugated bile salts with a pK a of 1-2, predominantly found in the rodent bile salt pool, 11 is sensitive to changes in biliary pH near the physiologic range. Protonation led to diffusional penetration and subsequent apoptotic cell death in the experimental setting used by us.…”

Section: Discussionmentioning

confidence: 64%

“…7 Human biliary HCO À 3 secretion accounts for 25%-40% of total bile flow and, by far, exceeds that of rodents. 8 The physiologic role of the enormous difference in biliary HCO À 3 secretion between humans and rodents has remained obscure. We recently hypothesized 7 that biliary HCO À 3 secretion might constitute a biliary HCO À 3 umbrella on the apical cholangiocyte surface, a, so far, unrecognized protective mechanism of cholangiocytes against bile-salt-induced toxicity.…”

mentioning

confidence: 99%

A biliary HCO₃⁻umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes

et al. 2011

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Human cholangiocytes are continuously exposed to millimolar levels of hydrophobic bile salt monomers. We recently hypothesized that an apical biliary HCO À 3 umbrella might prevent the protonation of biliary glycine-conjugated bile salts and uncontrolled cell entry of the corresponding bile acids, and that defects in this biliary HCO À 3 umbrella might predispose to chronic cholangiopathies. Here, we tested in vitro whether human cholangiocyte integrity in the presence of millimolar bile salt monomers is dependent on (1) pH, (2) adequate expression of the key HCO À 3 exporter, anion exchanger 2 (AE2), and (3) an intact cholangiocyte glycocalyx. To address these questions, human immortalized cholangiocytes and cholangiocarcinoma cells were exposed to chenodeoxycholate and its glycine/taurine conjugates at different pH levels. Bile acid uptake was determined radiochemically. Cell viability and apoptosis were measured enzymatically. AE2 was knocked down by lentiviral short hairpin RNA. A cholangiocyte glycocalyx was identified by electron microscopy, was enzymatically desialylated, and sialylation was quantified by flow cytometry. We found that bile acid uptake and toxicity in human immortalized cholangiocytes and cholangiocarcinoma cell lines in vitro were pH and AE2 dependent, with the highest rates at low pH and when AE2 expression was defective. An apical glycocalyx was identified on cholangiocytes in vitro by electron microscopic techniques. Desialylation of this protective layer increased cholangiocellular vulnerability in a pH-dependent manner. Conclusion: A biliary HCO À 3 umbrella protects human cholangiocytes against damage by bile acid monomers. An intact glycocalyx and adequate AE2 expression are crucial in this process. Defects of the biliary HCO À 3 umbrella may lead to the development of chronic cholangiopathies.

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“…Although significant progress has been achieved in understanding the mechanisms of canalicular bile secretion (1)(2)(3)(4)(5), knowledge is still incomplete, in part because the small size (1-2 um) and inaccessibility of the bile canaliculus in the intact liver precludes direct quantitative measurements of the primary secretion. Most studies of canalicular bile secretion have relied, therefore, on indirect methods including isolated perfused liver systems, where bile is sampled from biliary cannulas at distal sites after contact with and possible modification by bile ductules and ducts.…”

Section: Introductionmentioning

confidence: 99%

Quantitative assessment of canalicular bile formation in isolated hepatocyte couplets using microscopic optical planimetry.

Gautam

Ng²,

Strazzabosco³

et al. 1989

J. Clin. Invest.

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Mechanisms of Bile Secretion and Hepatic Transport

Cited by 11 publications

References 237 publications

A Nuclear Receptor-mediated Choleretic Action of Fibrates is Associated with Enhanced Canalicular Membrane Fluidity and Transporter Activity Mediating Bile Acid-independent Bile Secretion

A Nuclear Receptor-mediated Choleretic Action of Fibrates is Associated with Enhanced Canalicular Membrane Fluidity and Transporter Activity Mediating Bile Acid-independent Bile Secretion

A biliary HCO₃⁻umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes

Quantitative assessment of canalicular bile formation in isolated hepatocyte couplets using microscopic optical planimetry.

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Mechanisms of Bile Secretion and Hepatic Transport

Cited by 11 publications

References 237 publications

A Nuclear Receptor-mediated Choleretic Action of Fibrates is Associated with Enhanced Canalicular Membrane Fluidity and Transporter Activity Mediating Bile Acid-independent Bile Secretion

A Nuclear Receptor-mediated Choleretic Action of Fibrates is Associated with Enhanced Canalicular Membrane Fluidity and Transporter Activity Mediating Bile Acid-independent Bile Secretion

A biliary HCO3−umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes

Quantitative assessment of canalicular bile formation in isolated hepatocyte couplets using microscopic optical planimetry.

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A biliary HCO₃⁻umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes