REGULATION OF BILE-ACID SYNTHESIS .1. EFFECTS OF CONJUGATED URSODEOXYCHOLATE AND CHOLATE ON BILE-ACID SYNTHESIS IN CHRONIC BILE FISTULA RAT
REGULATION OF BILE-ACID SYNTHESIS .1. EFFECTS OF CONJUGATED URSODEOXYCHOLATE AND CHOLATE ON BILE-ACID SYNTHESIS IN CHRONIC BILE FISTULA RAT
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DOI：
10.1002/hep.1840080228
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发表时间：
1988-03-01
期刊：
影响因子：
13.5
通讯作者：
VLAHCEVIC, ZR
中科院分区：
文献类型：
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作者：
HEUMAN, DM;HERNANDEZ, CR;VLAHCEVIC, ZR
胆汁酸的合成被认为是由负反馈机制，这可能是依赖于胆汁酸在肠肝循环的流量调节。为了进一步表征胆汁酸在调节胆汁酸合成中的调节作用，我们通过连续十二指肠内输注给慢性胆瘘大鼠施用纯牛磺酸或熊去氧胆酸或胆酸的甘氨酸缀合物，从而模拟肝肠循环的恢复。这些胆盐输注对胆汁酸合成、胆汁胆固醇和磷脂分泌以及对肝微粒体酶胆固醇7 α-胆固醇的活性的影响羟化酶和HMG-CoA还原酶。因为在具有完整的外置式肠肝循环的大鼠中，胆汁盐分泌速率平均为27.1 ± 1.5。1.4每100克大鼠每小时24至36微摩尔，选择用于胆瘘研究的输注速率以匹配（每100克大鼠每小时24至36微摩尔）或超过（每100克大鼠每小时48微摩尔）该生理通量。以24和48 μ mol/100 gm大鼠/hr输注牛磺熊去氧胆酸48小时不能抑制胆酸合成。输注牛磺熊去氧胆酸后，胆汁流量和胆汁胆固醇和磷脂分泌表现出较小的剂量依赖性增加。不抑制胆固醇7 α-观察到羟化酶或HMG-CoA还原酶活性。相比之下，牛磺胆酸抑制鹅去氧胆酸盐及其代谢物α-的合成。和β-在24、36和48 μ mol/100 gm大鼠/hr的输注速率下，鼠胆酸盐分别增加10%（NS）、66%（p <0.05）和75%（p < 0.05）。以24、36和48 μ mol/100 gm大鼠/hr输注牛磺胆酸导致胆固醇7 α-胆固醇抑制30、34和32%。羟化酶活性。牛磺胆酸输注后，HMG-CoA还原酶活性与胆固醇7 α-CoA还原酶活性平行下降。羟化酶牛磺胆酸引起胆汁流量和胆固醇和磷脂的胆汁分泌显著的剂量依赖性增加。当牛磺胆酸输注速率为24、36和48 μ mol/100 gm大鼠/hr时，胆汁胆固醇分泌分别增加166、152和211%。牛磺熊去氧胆酸和牛磺胆酸均未引起总微粒体胆固醇含量的显著变化。我们的结论是，不同胆汁酸作为胆汁酸生物反馈的介体、胆汁胆固醇和磷脂分泌的促进剂以及胆固醇7 α-胆固醇的抑制剂的效力不同。羟化酶和HMG-CoA还原酶随其结构而变化，可能是其单体疏水性的函数。胆汁酸合成和胆汁脂质分泌之间存在明显的反比关系，表明调节胆固醇和胆汁酸合成的关键肝微粒体酶的活性可能通过改变微粒体膜的脂质组成或流动性间接控制。
Bile acid synthesis is thought to be regulated by a negative feedback mechanism which is presumably dependent upon the flux of bile acids in the enterohepatic circulation. To characterize further the role of bile acids in regulation of bile acids in regulation of bile acid synthesis, we have administered pure taurine or glycine conjugates of ursodeoxycholic acid or cholic acid to chronic bile fistula rats by continuous intraduodenal infusion, thus simulating restoration of the enterohepatic circulation. The effects of these bile salt infusions on bile acid synthesis, biliary cholesterol and phospholipid secretion and on the activities of the hepatic microsomal enzymes cholesterol 7.alpha.-hydroxylase and HMG-CoA reductase were evaluated. Because the rate of biliary bile salt secretion in rats with intact exteriorized enterohepatic circulation averaged 27.1 .+-. 1.4 .mu.moles per 100 gm rat per hr, infusion rates for bile fistula studies were chosen to match (24 to 36 .mu.moles per 100 gm rat per hr) or exceed (48 .mu.moles per 100 gm rat per hr) this physiological flux. Infusion of tauroursodeoxycholic acid for 48 hr at 24 and 48 .mu.moles per 100 gm rat per hr failed to suppress cholic acid synthesis. Bile flow and biliary cholesterol and phospholipid secretion exhibited small, dose-dependent increases with tauroursodeoxycholic acid infusions. No suppression of cholesterol 7.alpha.-hydroxylase or HMG-CoA reductase activity was observed. By contrast, taurocholic acid inhibited synthesis of chenodeoxycholate and its metabolites .alpha.- and .beta.-muricholate by 10% (NS), 66% (p < 0.05) and 75% (p < 0.05) at infusion rates of 24, 36 and 48 .mu.moles per 100 gm rat per hr, respectively. Taurocholic acid infusion at 24, 36 and 48 .mu.moles per 100 gm rat per hr resulted in 30, 34 and 32% suppression of cholesterol 7.alpha.-hydroxylase activity, respectively. After taurocholic acid infusion, HMG-CoA reductase activity declined in parallel with cholesterol 7.alpha.-hydroxylase. Taurocholic acid caused a pronounced, dose-dependent increase in bile flow and in biliary secretion of cholesterol and phospholipid. Biliary cholesterol secretion increased 166, 152 and 211%, respectively, with taurocholic acid infusion rates of 24, 36 and 48 .mu.moles per 100 gm rat per hr. With the same infusion rates, phospholipid secretion increased by 128, 267 and 510%. Neither tauroursodeoxycholic acid nor taurocholic acid caused a significant change in total microsomal cholesterol content. We conclude that the potency of different bile acids as mediators of bile acid biofeedback, promoters of biliary cholesterol and phospholipid secretion, and suppressors of cholesterol 7 .alpha.-hydroxylase and HMG-CoA reductase, varies with their structure, possibly as a function of their monomeric hydrophobicity. The existence of an apparent inverse relationship between bile acid synthesis and biliary lipid secretion suggests that the activities of the key hepatic microsomal enzymes regulating cholesterol and bile acid synthesis may be controlled indirectly via changes in the lipid composition or fluidity of the microsomal membranes.