Ursodeoxycholic Acid Is Conjugated with Taurine to Promote Secretin-Stimulated Biliary Hydrocholeresis in the Normal Rat

Abstract

Background & AimsSecretin induces bicarbonate-rich hydrocholeresis in healthy individuals, but not in untreated patients with primary biliary cirrhosis (PBC). Ursodeoxycholic acid (UDCA) – the first choice treatment for PBC – restores the secretin response. Compared with humans, secretin has poor effect in experimental normal-rat models with biliary drainage, although it may elicit hydrocholeresis when the bile-acid pool is maintained. In view of the benefits of UDCA in PBC, we used normal-rat models to unravel the acute contribution of UDCA (and/or taurine-conjugated TUDCA) for eliciting the biliary secretin response.MethodsIntravascular and/or intrabiliary administration of agonists and inhibitors was performed in normal rats with biliary monitoring. Secretin/bile-acid interplay was analyzed in 3D cultured rat cholangiocytes that formed expansive cystic structures with intralumenal hydroionic secretion.Results In vivo, secretin stimulates hydrocholeresis upon UDCA/TUDCA infusion, but does not modify the intrinsic hypercholeretic effect of dehydrocholic acid (DHCA). The former effect is dependent on microtubule polymerization, and involves PKCα, PI3K and MEK pathways, as shown by colchicine (i.p.) and retrograde biliary inhibitors. In vitro, while secretin alone accelerates the spontaneous expansion of 3D-cystic structures, this effect is enhanced in the presence of TUDCA, but not UDCA or DHCA. Experiments with inhibitors and Ca2+-chelator confirmed that the synergistic effect of secretin plus TUDCA involves microtubules, intracellular Ca2+, PKCα, PI3K, PKA and MEK pathways. Gene silencing also demonstrated the involvement of the bicarbonate extruder Ae2.ConclusionsUDCA is conjugated in order to promote secretin-stimulated hydrocholeresis in rats through Ae2, microtubules, intracellular Ca2+, PKCα, PI3K, PKA, and MEK.

The ascending pathophysiology of cholestatic liver disease

“…Pharmacokinetic tests to detect impairment of hepatobiliary secretion, using 11 C-labeled BS derivatives and dynamic positron emission tomographic scanning, (85) TUDCA (86) INT 777 (87) Recommended and approved for PBC PSC, 01755507 PBC, 01829698, 01857284 Not yet in trial 2 3 Increase phospholipid secretion PPARa agonists Fenofibrate (88) Bezafibrate (89) Abbreviations: ASBT, apical sodium-dependent BS transporter; CCR, chemokine (C-C motif) receptor; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NCT, National Clinical Trial; PPAR, peroxisome proliferator-activated receptor; TNF, tumor necrosis factor; VAP1, vascular adhesion protein 1.…”

Proposed therapies in primary biliary cholangitis

“…Another agent targeting bile acids, tauroursodeoxycholic acid (TUDCA) promotes bicarbonate-rich hypercholeresis and may have benefits over UDCA [42]. TUDCA was studied in a recent randomized controlled trial in China (NCT01829698) with the results yet to be published [43]. Further, 24-nor-UDCA, a side-chain shortened derivate of UDCA inducing a bicarbonate-rich hypercholeresis and which in experimental models of cholestasis has a pronounced anti-inflammatory and anti-fibrotic effect [44, 45] is currently under investigation in a double-blind, randomized, placebo-controlled phase II trial in patients with primary sclerosing cholangitis is ongoing (NCT01755507).…”

Роль Мікро-Рнк При Захворюваннях Біліарної Системи

“…Руйнування клітин жовчних проток при за-хворюваннях біліарної системи супроводжується розвитком холестазу, запалення та в подальшому фіброзу, цирозу печінки [32,37]. Холангіоцити є епітеліальними клітинами, що становлять 30 % від пулу клітин жовчних проток та до 3-5 % від загаль-ної популяції клітин печінки [38].…”

“…Холангіоцити беруть участь у загальних секреторних процесах шляхом зміни складу та руху по жовчних протоках первинної жовчі, що генерується в канальцях гепа-тоцитів. Транспорт води, іонів та розчинених речо-вин із крові у просвіт жовчних шляхів призводить до підлужування жовчі [37][38][39]. Епітеліальні кліти-ни жовчних проток частково або повністю страж-дають при захворюваннях біліарної системи, етіо-патогенез яких може мати різноманітний характер.…”