核受体FXR依赖胆汁酸信号对胆汁酸代谢的调节

法尼酯衍生物X受体(famesoid X receptor,FXR)是核受体的超家族成员之一,在多种代谢途径中起着关键作用.胆汁酸是FXR的主要内源性配体,激活的FXR作用于靶基因后具有抑制胆汁酸的合成、吸收和促进分泌等作用.本文就FXR在胆汁酸代谢过程中的靶基因及其功能进行总结.     

The effect of bile acid synthesis on cholesterol secretion into the bile.

Cholesterol secretion into the bile has been shown to be related to the bile acid secretion rate. It has been suggested that the availability of bile acid micelles controls the entry of cholesterol into the bile. However, previous data could have been interpreted to indicate that bile acid synthesis controls cholesterol secretion into the bile. To discover whether bile acid synthesis has a significant influence on cholesterol secretion, Rhesus monkeys were studied during the period of increasing bile acid secretion and bile acid synthesis, which begins 6-10 hours following interruption of the enterohepatic circulation of bile acids. This is the only condition in which bile acid synthesis and bile acid secretion increase simultaneously. The cholesterol secretion rate fell signficantly during this period, and this effect was enhanced by phenobarbital administration. An increasing cholesterol secretion rate would have been expected if micellar attraction controlled cholesterol secretion under these conditions. Bile acid synthesis appears to have an important influence upon cholesterol secretion into the bile.     

AMPK在胆汁酸代谢中的调节作用

腺苷酸活化蛋白激酶的激活可以抑制胆固醇、脂肪的合成,最近研究表明,腺苷酸活化蛋白激酶的激活也可抑制胆汁酸合成及促进胆盐输出泵的生成,说明腺苷酸活化蛋白激酶在调节胆汁酸代谢中起着重要作用.本文将从腺苷酸活化蛋白激酶激活途径、胆汁酸代谢、腺苷酸活化蛋白激酶活性对胆汁酸合成及转运等方面进行综述.     

Repetitive short-term bile duct obstruction and relief causes reproducible and reversible bile acid regurgitation

BACKGROUND: Long-term bile duct obstruction causes sinusoidal regurgitation of bile acids, a shift in bile acid metabolism, and alterations of liver histology. In this study we investigated the regurgitation of bile acids during short-term bile duct obstruction and its reversibility and reproducibility. In addition, the biotransformation of taurodeoxycholate and its appearance in bile and perfusate effluent were studied as well as liver histology. METHODS: Rat livers (n = 5) were perfused in vitro with 32 nmol/min/g liver taurodeoxycholate over 85 min with the bile duct being intermittently closed for 30 and 20 min, respectively. RESULTS: Within the first 5 min after bile duct obstruction bile acids started to regurgitate to the perfusate effluent amounting to approximately 15% of hepatic uptake until the end of the perfusion period. After relief of obstruction, bile flow and biliary bile acid excretion showed an overshoot phenomenon and were almost doubled compared to preobstruction. In contrast, sinusoidal bile acid regurgitation declined. The same phenomenon was observed during the second closure/opening cycle of the bile duct. Regurgitated bile acids consisted of significantly more taurodeoxycholate metabolites (approximately 70%) than did biliary bile acids (approximately 30%). Histology of liver parenchyma was preserved. CONCLUSIONS: During repetitive short-term bile duct obstruction bile acid regurgitation is reversible and reproducible. The absence of altered mechanical barriers suggests that specific pathways are involved in the regurgitation process of bile acids.     

Medical dissolution of gallstones by oral bile acid therapy

The rationale, safety, and efficacy of cholesterol gallstone dissolution by orally administered ursodiol, chenodiol, or a combination of the two agents are summarized herein. Bile must be supersaturated in cholesterol for gallstones to form, and desaturation of bile by orally administered bile acids induces gradual stone dissolution. The mechanism of action of the two agents differs, but both cause a decreased input of cholesterol into the metabolic pool. Ursodiol is free of side effects, and the combination with chenodiol is equally efficacious and also has few side effects. Chenodiol, although an effective desaturation agent, causes diarrhea, mild reversible hepatic injury, and a small increase in the plasma cholesterol level. Extracorporeal shock-wave lithotripsy decreases gallstone size markedly and thereby increases the speed of dissolution by orally administered bile acids. Medical therapy with oral bile acids is appropriate for patients who present with small cholesterol stones and for patients with larger cholesterol gallstones who cannot or will not have surgery. Oral bile acids may also be valuable in the treatment of gallstone recurrence before it has become symptomatic or to prevent recurrence after prior successful dissolution of recurrent stones.     

Role of bile acid reflux in acute hemorrhagic gastritis

A model was developed to assess the influence of bile acids on the ability of proximal canine gastric mucosa to maintain an intraluminal pH gradient and to resist acute morphologic injury. It was found that the combination of topical acid, topical bile acid, and mucosal ischemia is acutely and severely ulcerogenic. Lesion severity is a function of the absolute amount of H⁺; diffusing into the mucosa which is, itself, a function of the intraluminal concentrations of both bile and H⁺. Morphologic injury is associated with the development of a marked gastric venous acidosis. Bile acid species differ in their capacity to induce lesions. Topical application of bile acids to nonischemic mucosa is not acutely ulcerogenic because a compensatory increase in mucosal blood flow occurs which is proportional to the degree of H⁺ loss induced. In the present model, steroids are cytoprotective by virtue of this mechanism, while histamine H₁ and H₂ receptor antagonists, either along or in combination, are not. The clinical applicability of these findings is discussed.

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Résumé Un modèle expérimental a été mis au point pour évaluer l'influence des acides biliaires sur la muqueuse gastrique fundique du chien. Nous voulions étudier la capacité de cette muqueuse à maintenir un gradient de pH vers la lumière digestive et sa résistance à 1'aggression biliaire. Lorsque la muqueuse est baignée par une solution acide et des acides biliaires et qu'elle est, de plus, en ischémie, des ulcerations aiguës et graves apparaissent. La gravité des lésions est fonction de la quantité absolue d'H+ diffusant dans la muqueuse qui est, ellemême, proportionnelle aux concentrations intraluminales d'acides biliaires et d'H+. Le développement des lésions est concomittant d'une acidose veineuse importante dans la muqueuse gastrique. La capacité de produire des lésions est variable pour les divers acides biliaires. L'application locale d'acides biliaires sur une muqueuse non ischémiée ne provoque pas l'apparition d'ulcerations aiguës, par un accroissement compensatoire du flux sanguin muqueux qui est proportionnel à l'importance de la perte d'H+. Par le même mécanisme, les stéroides sont cytoprotecteurs dans le modèle étudié, alors que les antagonistes des récepteurs H1 et H2, seuls ou combinés, ne le sont pas. L'application clinique de ces données est discutée.

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Supported by United States Public Health Service Grant No. AM17591 and Department of the Army Grant No. 17-74-C-4014.     

Decreased bile acid synthesis with total parenteral nutrition

BACKGROUND: Biliary changes occur in patients on total parenteral nutrition (TPN) predisposing them to gallstones and cholestasis. We hypothesized that patients on TPN, similar to animal models, would have reduced bile acid synthesis. METHODS: Serum from 13 controls and 17 patients on TPN were collected and tested with HPLC for 7alpha-hydroxy-4-cholesten-3-one, which has been shown to correlate with bile acid synthesis. Somatostatin and tumor necrosis factor alpha levels were determined with enzyme-linked immunosorbent assays. RESULTS: Bile acid synthesis was significantly reduced in patients on TPN. TPN patients on oral feeding (but not jejunostomy) had similar bile acid synthesis rates as controls. In patients on TPN and nothing by mouth, somatostatin had a significant negative correlation with bile acid synthesis (P < .01). CONCLUSION: TPN patients have a reduced bile acid synthesis, and this correlates with somatostatin if they are treated with nothing by mouth. Oral feeding is associated with a higher bile acid synthesis, and body mass index, age, albumin, and tumor necrosis factor alpha do not have an effect on bile acid synthesis.     

胆囊黏膜G蛋白偶联胆汁酸受体1表达与胆囊结石致石胆汁关系的研究

目的 研究胆囊结石患者胆囊黏膜G蛋白偶联胆汁酸受体1 (GPBAR1)表达与致石胆汁形成的关系.方法 收集34例胆囊结石病和15例无胆石对照患者的胆囊黏膜、囊壁、胆汁、静脉血.HE常规染色病理检查胆囊壁,免疫组化染色法检测胆囊壁GPBAR1、黏蛋白1(MUC1)和黏蛋白5AC(MUC5AC)的表达水平;RT-PCR反应检测胆囊黏膜GPBAR1、MUC1和MUC5AC的基因表达水平;检测术前血清和胆囊胆汁的主要脂质成分等.结果 胆囊结石组胆囊HE染色均呈慢性炎症表现;胆囊结石组GPBAR1、MUC5AC的蛋白和mRNA表达均较对照组明显升高(61.34±8.06比43.05±7.83,P＜0.01; 52.11±9.62比45.05±9.27,P＜0.05;0.87±0.07比0.80±0.09,P＜0.05;1.04±0.22比0.8±0.17,P＜0.01).胆囊结石组血清总胆固醇水平和胆汁总胆固醇浓度、总胆固醇摩尔百分比、胆固醇饱和指数、黏蛋白浓度均较对照组明显升高(5.07±1.64比3.62±1.42,P＜0.01;17.23±3.67比12.47±2.31,P＜0.01;7.47±0.65比5.05±0.24,P＜0.01;1.03±0.58比0.69±0.38,P＜0.01;92.02±20.89比76.36±19.71,P＜0.05);而胆汁总胆汁酸浓度、胆汁酸摩尔百分比较对照组明显降低(162.68±20.19比180.21±26.05,P＜0.05; 71.28±1.84比73.29±0.96,P＜0.01).胆囊结石组胆囊GPBAR1 mRNA表达与胆汁总胆汁酸水平负相关(γ=-0.341,P＜0.05),GPBAR1表达与胆汁总胆汁酸水平和总脂质水平均负相关(γ=-0.365,P＜0.05;γ=-0.403,P＜0.05).结论 GPBAR1在胆囊结石患者胆囊黏膜表达增强,介导胆汁酸吸收,可能与致石胆汁形成有关.     

Influence of tacrolimus on bile acid and lipid composition in continuously drained bile using a rat model

Cholestatic effects have been reported for cyclosporine (CsA), but information is still limited for tacrolimus (TCR). The purpose of this study was to investigate the influence of TCR on biliary bile acid and lipid composition as compared with CsA, using a continuously bile-drained rat model. Adult male Wistar rats received TCR (0.4 mg/kg, 1 mg/kg, and 4 mg/kg) or CsA (2.5 mg/kg, 10 mg/kg, and 25 mg/kg) by intramuscular injection (i. m.) daily for 10 days. On day 7, the common bile duct of all rats was cannulated, then bile was continuously collected for the following 3 days. Bile flow, bile acid secretion rate (BASR), and biliary lipids secretion were measured for each of the groups. TCR increased bile acid-dependent flow (BADF) but with no statistical significance. However, this agent did not influence total bile flow and biliary lipids secretion, while bile acid-independent flow (BAIF) was significantly reduced and bile acid synthesis (mainly cholic acid, CA, synthesis) was increased. In contrast, CsA was cholestatic, showing a tendency to reduce both BADF and BAIF. BASR was dose-dependently suppressed, especially in chenodeoxycholic acid (CDCA). Furthermore, biliary lipids secretions were also significantly decreased under a higher dose of CsA. TCR increased BADF with no influence on total bile flow, having a stimulating effect on CA production, although CsA dose-dependently diminishes CDCA production and consequently reduced bile secretion. Our results suggest that TCR is a less effective agent on cholestasis as compared to CsA. Received: 24 August 1998 Received after revision: 12 January 1999 Accepted: 3 March 1999     

Biliary bile acid profiles in familial adenomatous polyposis.

Patients with familial adenomatous polyposis have an excess risk for adenomas and cancers of the upper and lower gastrointestinal tract. In the upper intestine these lesions occur mainly around the ampulla of Vater and they parallel mucosal exposure to bile. In view of this finding and of evidence that bile acids play a role in colorectal carcinogenesis, biliary bile acid profiles were determined in 29 patients with familial adenomatous polyposis (12 before colectomy, 17 after colectomy) and in 28 patients without familial adenomatous polyposis (all with colons in situ). Patients with familial adenomatous polyposis had a higher total biliary bile acid concentration than the others. The bile of patients with polyposis had a greater proportion of chenodeoxycholic acid and a lower proportion of deoxycholic acid than did the bile of patients without polyposis. The ratio of chenodeoxycholic acid and its metabolite lithocholic acid to cholic acid and its metabolite deoxycholic acid, which is related to subsequent bile acid profiles in the colon, was higher in patients with polyposis. Because bile acids influence cellular proliferation, these findings may be of importance with respect to intestinal adenoma and cancer growth.     

Conditioning of liver grafts with prostaglandins improves bile acid transport

INTRODUCTION: Conditioning of liver grafts by bolus pretreatment with prostaglandins has been previously demonstrated to improve hepatic bile flow. However, the underlying mechanisms have not been investigated. To elucidate whether improved bile flow after prolonged ischemia is due to maintained bile acid secretion or due to increased paracellular permeability, we performed a study using increasing doses of the marker acid taurocholate in the isolated perfused rat liver system. METHODS: Livers were harvested from adult Lewis rats and stored for 24 hours in UW solution. Pretreatment of livers was performed 1 minute before preservation. One group received prostaglandin I2, the second group received prostaglandin E1, and the control group was treated with saline. After 24 hours of cold storage the grafts were investigated in the isolated perfused rat liver system by perfusion with an oxygenated Krebs-Ringer-Henseleit buffer. Increasing doses of the radiolabeled marker bile acid taurocholate were infused to investigate bile acid transport. RESULTS: Bile flow and bile acid output were increased by pretreatment of the livers with prostaglandin I2 and prostaglandin E1, as compared to the control group. More specifically, the maximum transport rate was tripled by prostaglandin I2 and by prostaglandin E1 preconditioning of liver grafts, in comparison to the control group (P < .01 vs prostaglanin I2 and E1). CONCLUSION: The results clearly demonstrate that increased bile flow after conditioning of liver grafts with prostaglandins is not due to increased paracellular permeability but is based on markedly improved bile acid output.     

Role of acid and bile in the genesis of Barrett's esophagus

Clinical and experimental studies have shown that acid and bile reflux are increased in patients who have Barrett's esophagus. The combination of both seems the key factor in the pathogenesis of Barrett's esophagus. This factor has been confirmed by immunohistochemical studies that show that environmental factors, such as acid and bile, are involved in the pathogenesis of Barrett's esophagus. There is a critical pH range between 3 and 6 in which bile acids exist in their soluble, un-ionized form; can penetrate cell membranes; and accumulate within mucosal cells. At a lower pH, bile acids are precipitated, and at a higher pH, bile acids exist in their noninjurious ionized form. Thus incomplete gastric acid suppression, as is the case with most medical treatment regimens for gastroesophageal reflux, may in fact predispose to the development of Barrett's esophagus.