Effect of high plant sterol-enriched diet and cholesterol absorption inhibitor, SCH 58235, on plant sterol absorption and plasma concentrations in hypercholesterolemic wild-type Kyoto rats.
Effect of high plant sterol-enriched diet and cholesterol absorption inhibitor, SCH 58235, on plant sterol absorption and plasma concentrations in hypercholesterolemic wild-type Kyoto rats.
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富含植物甾醇的高饮食和胆固醇吸收抑制剂 SCH 58235 对高胆固醇血症野生型京都大鼠植物甾醇吸收和血浆浓度的影响。
DOI：
10.1016/j.metabol.2004.08.004
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Salen,Gerald
中科院分区：
文献类型：
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作者：
Batta,AshokK;Xu,Guorong;Bollineni,JayaS;Shefer,Sarah;Salen,Gerald
背景和目的植物甾醇广泛分布于人类饮食中，但吸收不良，因此其血浆水平非常低。然而，当大量喂食时，它们通过干扰胆固醇吸收来降低血浆胆固醇水平。我们已经研究了4周的效果喂养的饲料补充了1%的植物甾醇[菜籽甾醇（6.3%），菜油甾醇（28.5%），豆甾醇（15.6%）和谷甾醇（49.6%）]，联合或不联合SCH 58235（依折麦布的衍生物），30 mg/kg/天，已知可抑制肠道胆固醇吸收，对血浆、组织、胆汁方法Wistar和野生型京都（WKY）大鼠经静脉给予[3α-3 H]谷甾醇和经口给予[4- 14 C]谷甾醇，分别于给药后1、2、3、4、5、6、7、8、10、12、24、26、28、29、标记后5天测定谷甾醇吸收。在最后3天收集粪便并冷冻干燥。在喂养结束时，在每种品系的3只大鼠中建立胆汁瘘，并收集胆汁1小时。然后处死所有大鼠，收集血浆和肝脏用于固醇测量和肝HMG-CoA还原酶、胆固醇7α-羟化酶和胆固醇27-羟化酶的活性。血浆胆固醇往往是较低的WKY大鼠喂养植物甾醇丰富的饮食后，而植物甾醇水平上升到约31%的WKY和14%的Wistar大鼠血浆甾醇。然而，在C-22处具有双键的油菜甾醇和豆甾醇占血浆植物甾醇总量的不到3.5%。喂食后，Wistar大鼠的胆汁植物甾醇增加了2.25倍，WKY大鼠增加了1.5倍，表明WKY大鼠的肝脏清除率较低。SCH 58235饲喂显著增加了未给药和植物甾醇饲喂的WKY大鼠的血浆和胆汁胆固醇水平，血浆植物甾醇显示出增加的趋势，但未达到显著水平。两种大鼠品系的肠道细菌将所有植物甾醇代谢为主要的5β-H-甾烷醇。然而，C-22双键对细菌降解是稳定的。肠道吸收谷甾醇和胆固醇增加1.5和1.3倍，分别在WKY大鼠相比，Wistar大鼠，和植物甾醇喂养降低吸收这些甾醇在两个菌株。在两种品系中，SCH 58235给药大鼠对这两种甾醇的吸收也降低，当同时饲喂SCH 58235和植物甾醇时，吸收进一步降低。与未处理大鼠相比，Wistar大鼠和WKY大鼠的限速酶HMG-CoA还原酶活性分别增加了1.57倍和1.27倍。结论（1）WKY大鼠对植物甾醇的吸收增加，而肝脏对所有甾醇的清除减少，这是胆固醇和植物甾醇水平升高的原因。(2)在WKY大鼠中，1%植物甾醇富集饲料倾向于降低血浆胆固醇水平，而SCH 58235喂养显著增加血浆胆固醇水平。(3)具有C-22双键的甾醇的肠道吸收减少，侧链双键对肠道细菌具有抗性。
BACKGROUND AND AIMSPlant sterols are widely distributed in human diet but are poorly absorbed so that their plasma levels are very low. However, when fed in large amounts, they lower plasma cholesterol levels by interfering with cholesterol absorption. We have studied the effect of 4 weeks of feeding a chow diet supplemented with 1% plant sterols [brassicasterol (6.3%), campesterol (28.5%), stigmasterol (15.6%) and sitosterol (49.6%)], with or without SCH 58235 (a derivative of ezetimibe), 30 mg/kg per day, known to suppress intestinal cholesterol absorption, on plasma, tissue, biliary, and fecal sterols in Wistar and wild-type Kyoto (WKY) rats, and their metabolism by intestinal bacteria.METHODSAfter 2 weeks of feeding control or experimental diet, rats were given [3α-3H]sitosterol intravenously and [4-14C]sitosterol by mouth, and blood was collected after 1, 2, 3, and 5 days after labeling to determine sitosterol absorption. Feces were collected during the last 3 days and freeze dried. At the end of feeding, bile fistulas were created in 3 rats of each strain and bile was collected for 1 hour. All rats were then sacrificed and plasma and liver were collected for sterol measurements and activities of hepatic HMG-CoA reductase, cholesterol 7α-hydroxylase, and cholesterol 27-hydroxylase.RESULTSWild-type Kyoto rats were hypercholesterolemic compared to Wistar rats and had increased plant sterols in the plasma. Plasma cholesterol tended to be lower in WKY rats after feeding with plant sterol-enriched diet whereas plant sterol levels rose to approximately 31% of plasma sterols in WKY and 14% in Wistar rats. However, brassicasterol and stigmasterol, with a double bond at C-22, constituted less than 3.5% of total plasma plant sterols. After feeding, biliary plant sterols increased 2.25-fold in Wistar and 1.5-fold in WKY rats, suggesting less hepatic clearance in WKY rats. SCH 58235 feeding significantly increased plasma as well as biliary cholesterol levels in both the untreated and plant sterol-fed WKY rats, and the plasma plant sterols showed a tendency to increase but did not reach significant level. Intestinal bacteria in both rat strains metabolized all plant sterols to mainly the 5β-H-stanols. However, the C-22 double bond was stable to bacterial degradation. Intestinal absorption of sitosterol and cholesterol was increased 1.5- and 1.3-fold, respectively, in the WKY rats as compared to the Wistar rats, and plant sterol feeding lowered absorption of these sterols in both strains. Absorption of both these sterols was also lowered in SCH 58235-treated rats in both strains and was further lowered when SCH 58235 and plant sterols were simultaneously fed. The activity of the rate-limiting enzyme, HMG-CoA reductase, was increased 1.57-fold in Wistar rats and 1.27-fold in WKY rats that were fed plant sterols as compared to untreated rats.CONCLUSIONS(1) Plant sterol absorption was increased whereas hepatic elimination of all sterols was diminished in WKY rats accounting for elevated cholesterol and plant sterol levels. (2) The 1% plant sterol-enriched diet tended to lower plasma cholesterol levels whereas SCH 58235 feeding significantly increased plasma cholesterol levels in the WKY rats. (3) Intestinal absorption of sterols with C-22 double bond is diminished and the side-chain double bond is resistant to intestinal bacteria.