推按运经仪对家兔胆囊壁胆囊收缩素受体基因表达的影响

[目的]观察推按运经仪对家兔胆囊壁胆囊收缩素(CCKA)受体基因表达的影响及其作用机制.[方法]将30只胆囊结石家兔随机分为2组,各15只,对照组不行推按运经仪治疗;实验组空腹时每日行推按运经仪治疗,观察2组胆囊体积和胆囊壁CCK-A受体基因表达的差异.[结果]实验组胆囊体积明显小于对照组,而胆囊平滑肌CCK A受体基因表达明显大于对照组,差异均有统计学意义(P＜0.05).[结论]推按运经仪治疗胆囊结石可增强胆囊壁CCK-A受体基因表达,加强胆囊收缩,可能是其防治胆囊结石的作用机制之一.     

胆胃舒冲剂对胆囊息肉摘除术后复发的影响

[目的]观察利胆健脾中药胆胃舒冲剂对保胆息肉摘除术后患者息肉复发的影响.[方法]将138例患者随机分成2组,对照组单纯采用保胆内镜息肉摘除术治疗,治疗组在内镜摘除术治疗基础上加服利胆健脾中药胆胃舒冲剂.1年后观察2组息肉复发情况、胆囊收缩功能及胆囊壁厚度.[结果]治疗组对胆囊壁厚度、胆囊收缩功能(相对收缩率)方面的影响优于对照组(P＜0.01)；治疗组未发现息肉复发,对照组复发1例.[结论]胆胃舒冲剂能增强胆囊收缩功能及使胆囊壁厚度变薄,能预防胆囊息肉的复发.     

胆胃舒冲剂对经皮穿刺保胆息肉摘除术后复发的预防作用

[目的]观察胆胃舒冲剂对经皮穿刺保胆息肉摘除术后复发的预防作用。[方法]将118例患者随机分成2组，各59例。对照组单纯采用在B超引导下经皮穿刺保胆内镜息肉摘除术治疗，治疗组在内镜治疗基础上加服中药胆胃舒冲剂。1年后观察2组息肉复发情况、胆囊收缩功能及胆囊壁厚度。[结果]治疗组胆囊壁厚度显著低于对照组；胆囊收缩功能则高于对照组（均P〈0.05）；治疗组未发现息肉复发，对照组复发2例。[结论]胆胃舒冲剂能增强胆囊收缩功能并使胆囊壁厚度变薄，可预防胆囊息肉的复发。     

通脉汤方对实验性动脉粥样硬化家兔胸主动脉表皮生长因子受体和c-myc基因表达的影响

目的探讨通脉方对实验性动脉粥样硬化家兔胸主动脉表皮生长因子受体和c-myc基因表达的影响。方法日本大耳白兔40只,随机分为4组:①对照组10只,以普通饲料喂养,每日两次;②模型组10只,以高胆固醇饲料[胆固醇0.5g/(kg.d)、蛋黄2g/(kg.d)和猪油2g/(kg.d)]喂养,每日两次;③通脉汤方低剂量组(简称低剂量组)10只,高胆固醇饲料喂养(剂量同模型组),同时予通脉汤方灌胃,每只剂量相当于生药7.3g/(kg.d),分上下午两次给药;④通脉汤方高剂量组(简称高剂量组)10只,高胆固醇饲料喂养(剂量同模型组),同时予通脉汤方灌胃,每只剂量相当于生药21.9g/(kg.d),分上下午两次给药;共喂养16周。运用免疫组织化学染色法检测主动脉表皮生长因子受体的表达,同时用内参比逆转录聚合酶链反应定量分析c-mycmRNA在主动脉的表达。结果模型组主动脉表皮生长因子受体及c-mycmRNA表达显著高于对照组(分别为0.327±0.030比0.209±0.006,P<0.01;0.52±0.11比0.34±0.07,P<0.01);高剂量组主动脉表皮生长因子受体及c-mycmRNA表达显著低于模型组(分别为0.242±0.014比0.327±0.030,P<0.01;0.41±0.07比0.52±0.11,P<0.05);低剂量组与模型组比较无显著差异(分别为0.301±0.027比0.327±0.030P>0.05;0.44±0.09比0.52±0.11P>0.05)。结论①动脉粥样硬化时促进血管平滑肌细胞增殖的表皮生长因子受体及原癌基因c-mycmRNA表达增强。②通脉汤方通过抑制血管壁表皮生长因子受体及c-myc基因的表达,从而抑制血管平滑肌细胞增殖。     

防石胶囊预防胆囊结石复发的临床研究

[目的]观察中药防石胶囊预防微创保胆内镜取石术后患者胆囊结石复发的效果。[方法]将178例行微创保胆取石术后患者随机分成对照组及治疗组,每组89例,分别予不同治疗,2年后计算胆囊壁的厚度及胆囊收缩功能的变化。[结果]治疗组胆囊壁厚度显著低于对照组,收缩功能则高于对照组（P〈0.01）,对照组有3例结石复发。[结论]防石胶囊能减轻及消除胆囊壁的炎症,增强胆囊的收缩功能,有助于防止胆囊结石的复发。     

微创保胆取石术联合牛磺熊去氧胆酸预防胆囊结石复发效果观察

目的：观察牛磺熊去氧胆酸（TUDCA）降低微创保胆取石术后胆囊结石复发的临床效果。方法42例胆囊结石患者被随机分为单纯保胆手术组21例和联合治疗组21例,联合治疗组在微创保胆取石术后口服 TUDCA,每个月连续服用5天后,停止口服25天,为期1年。比较两组患者胆囊结石复发率、胆囊壁厚度及胆囊收缩功能的变化。结果在术后2年,单纯手术组患者胆囊结石症状复发率为33.3%（7/21）,显著高于联合治疗组患者的4.8%（1/21）。单纯手术组5例（23.8%）胆囊结石复发,而加服药物组无复发（x2=5.6757,P〈0.05）;单纯手术组患者术前和术后胆囊壁厚度分别为（3.95±0.56） mm 和（3.74±0.68）mm,胆囊收缩功能分别为（38.24±4.33）%和（37.89±6.42）%,而加服药物组患者胆囊壁厚度分别为（2.88±0.67） mm 和（2.43±0.71） mm,胆囊收缩功能分别为（48.78±6.45）%和（59.46±3.64）%,其改善程度均显著优于单纯手术组（P〈0.05）。结论微创保胆取石术后联用 TUDCA 口服能有效降低胆囊结石的复发,改善胆囊收缩功能。     

胆囊收缩素对胆固醇结石豚鼠离体胆囊肌条的影响

目的:建立胆固醇结石实验动物模型,探讨胆囊收缩素(cholecystokinin,CCK)对胆固醇结石豚鼠离体胆囊肌条收缩的影响,并研究胆道动力因素在胆固醇结石形成中的作用.方法:喂养致石饲料构建豚鼠胆固醇结石模型.采用灌流法加药,利用张力换能器记录豚鼠离体胆囊肌条张力的变化,观察10-9、10-8、10-7 mol/L的CCK-8对正常豚鼠离体胆囊肌条(A组)、喂养致石饲料4 wk(B组)、8 wk(C组)豚鼠离体胆囊肌条及正常豚鼠损伤Caial间质细胞(interstitial cell of cajal,ICC)后离体胆囊肌条(D组)的影响.结果:A组无结石发生,B组及C组共有13例结石发生:A组、B组及C组加入CCK后收缩振幅均增加,呈浓度依赖性:B、C两组振幅加入CCK后的效应值同A组相比变小,起作用时间慢(P<0.05);损伤胆囊ICC后,收缩幅度增加不明显,与CCK浓度无显著差异,而与A组相比效应值有显著性差异(10-9mol/L:0.461±0.071 vs 1.461±0.252:10-8mol,L:0.608±0.118 vs 2.484±0.283:10-7mol/L:0.641±0.129 vs 3.312±0.311,均P<0.01).结论:离体胆囊肌条肌张力降低及对CCK的效应性降低在胆囊结石病的发生发展中有重要作用;而损伤ICC后,胆囊离体肌条对CCK的效应性明显降低,ICC可能在胆囊结石等胆囊动力性疾病中发生作用.     

非对称二甲基精氨酸促进大鼠主动脉氧化型低密度脂蛋白受体表达

目的观察非对称二甲基精氨酸对大鼠主动脉氧化型低密度脂蛋白受体表达的影响,探讨其在动脉粥样硬化中的作用。方法健康成年Wistar大鼠34只随机分为四组:①对照组(n=7)正常饲料喂养,正常饮水。②高脂饲料组(n=9)用高脂饲料喂养,正常饮水。③非对称二甲基精氨酸(简称甲基精氨酸)组(n=9)用高脂饲料喂养,饮水中按体重加入非对称二甲基精氨酸[0.2 mg/(kg.d)]。④L精氨酸组(n=9)用高脂饲料喂养,饮水中按体重加入非对称二甲基精氨酸[0.2 mg/(kg.d)]和L精氨酸[12 mg/(kg.d)]。18周后麻醉大鼠,取主动脉,以RT-PCR和Western blotting检测主动脉氧化型低密度脂蛋白受体mRNA和蛋白表达。结果①甲基精氨酸组氧化型低密度脂蛋白受体mRNA表达量(1.608±0.114)较对照组(0.363±0.027)和高脂饲料组(0.480±0.065)增加(P均<0.001),L精氨酸组氧化型低密度脂蛋白受体mRNA表达量(0.902±0.037)较甲基精氨酸组降低(P<0.01);②甲基精氨酸组氧化型低密度脂蛋白受体蛋白表达量(0.662±0.063)较对照组(0.111±0.022)和高脂饲料组(0.251±0.004)增加(P均<0.001),L精氨酸组(0.364±0.117)较甲基精氨酸组氧化型低密度脂蛋白受体蛋白表达降低(P<0.05)。结论非对称二甲基精氨酸促进大鼠主动脉氧化型低密度脂蛋白受体基因和蛋白表达,可能与非对称二甲基精氨酸促进动脉粥样硬化有关。     

胆淤方对胆汁淤积模型小鼠胆管周围炎与FXR1表达的影响

[目的]探讨胆淤方对胆汁淤积模型小鼠胆管周围炎及法尼醇X受体1(FXR1)表达的影响。[方法]72只雄性C57BL/6小鼠随机分为正常组(N)8只、模型组(M)12只、奥贝胆酸组(OCA)16只、胆淤方低剂量组(DJ)18只和胆淤方高剂量组(GJ)18只。N组小鼠饲料不含DDC,M、OCA、DJ和GJ组采用0.07%DDC饲料连续喂养8周。从第3周开始,OCA组予OCA溶液0.03 g/(kg·d)~(-1)灌胃,DJ组予胆淤方11 g/(kg·d)~(-1)灌胃,GJ组予胆淤方33 g/(kg·d)~(-1)灌胃,对照组给予相同体积的双蒸水灌胃处理。干预6周后收集各组小鼠血清及肝组织,试剂盒检测生化指标,苏木精-伊红染色观察肝内胆管周围炎,免疫组化观察细胆管反应和FXR1蛋白表达,WB检测FXR1蛋白表达量。[结果](1)M组ALT、AST、ALP和TBA水平较N组显著升高(P0.05);干预后,OCA、DJ和GJ组ALT、AST、ALP、TBA水平均较M组显著下降(P0.05);与OCA组比较,GJ组的ALT、AST水平下降更加显著(P0.05)。(2)苏木精-伊红染色示M组胆管周围大量炎性细胞浸润,OCA、DJ和GJ组胆管周围炎症较M组减轻。(3)CK19染色示M组汇管区大量细小胆管增生,OCA、DJ和GJ组胆管增生较M组减少。(4)FXR1染色和WB结果示OCA、DJ、GJ组FXR1表达量均较M组增多,以GJ组增加更显著。[结论]胆淤方具有减轻胆汁淤积模型小鼠胆管周围炎和激活FXR1表达的作用,这为研究胆淤方的药效机制提供依据。     

胆胃胶囊对大鼠胆汁反流性胃炎模型癌基因及相关因子的影响

[目的]研究胆胃胶囊对胆汁反流性胃炎模型的作用机制。[方法]SD大鼠72只随机分为6组,达喜阳性药组,胆胃胶囊大、中、小剂量组,另设假手术对照空白组和模型组比较,按组分别空腹灌胃给药,每日1次,连续给药14 d。第14天给药后取胃称重,以胃脏器系数代表水肿程度,并取贲门至幽门胃黏膜皮部和腺部做病理检查。免疫组化检测癌基因蛋白表达。[结果]模型组与空白组比较,胃脏器系数明显增加,表明造模成功。与模型组比较,阳性药组、胆胃胶囊大、中剂量组胃脏器系数明显减小。电镜观察,阳性药组与胆胃胶囊大、中剂量组显著减轻基底细胞增厚及腺上皮充血水肿;阳性药组与胆胃胶囊大剂量组也能明显改善黏液细胞下降及核大深染现象。差异均有统计学意义(P<0.05-<0.01)。胆胃胶囊大、中剂量组表皮生长因子受体表达明显增强,p21表达明显下降。[结论]胆胃胶囊能显著抑制胃黏膜充血、水肿,减轻基底细胞增厚和黏液细胞下降,上调胃黏膜表皮生长因子受体表达及下调p21表达。     

胆囊结石患者胆囊壁CCK-AR mRNA表达及血浆CCK-8水平与胆囊排空功能的关系

目的探讨胆囊结石患者胆囊收缩素(CCK)-A受体(AR)mRNA表达及血浆CCK-8水平与胆囊排空功能的关系。方法60例胆囊结石患者(结石组)和30例无胆囊结石而行上腹部手术者(对照组),术前用B超测定胆囊排空功能,RT-PCR技术检测胆囊壁CCK-ARmRNA,放射免疫法检测血浆CCK-8。结果结石组CCK-ARmRNA为0.59±0.11,与对照组的0.91±0.06相比,P<0.01;结石组中,胆囊收缩减弱者的CCK-ARmRNA为0.52±0.06,与收缩正常者的0.70±0.07相比,P<0.01;结石组血浆CCK-8为(42.91±2.88)pmol/L,与对照组的(31.50±1.62)pmol/L相比,P<0.05;结石组术前血浆CCK-8为(42.91±2.88)pmol/L,与术后的(34.21±2.56)pmol/L相比,P<0.05。结论CCK-AR、CCK-8在胆囊运动调节中发挥重要作用。     

Roles of sphincter of Oddi motility and serum vasoactive intestinal peptide,gastrin and cholecystokinin octapeptide

AIM:To investigate roles of sphincter of Oddi(SO)motility played in pigment gallbladder stone formation in model of guinea pigs.METHODS:Thirty-four adult male Hartley guinea pigs were divided randomly into two groups:the control group and pigment stone group.The pigment stone group was divided into 4 subgroups with 6 guinea pigs each according to time of sacrifice,and were fed a pigment lithogenic diet and sacrificed after 3,6,9 and 12wk.SO manometry and recording of myoelectric activity of the guinea pigs were obtained by multifunctional physiograph at each stage.Serum vasoactive intestinal peptide(VIP),gastrin and cholecystokinin octapeptide (CCK-8)were detected at each stage in the process of pigment gallbladder stone formation by enzyme-linked immunosorbent assay.RESULTS:The incidence of pigment gallstone formation was 0%,0%,16.7%and 66.7%in the 3-,6-,9-and 12-wk group,respectively.The frequency of myoelectric activity decreased in the 3-wk group.The amplitude of myoelectric activity had a tendency to decrease but not significantly.The frequency of the SO decreased significantly in the 9-wk group.The SO basal pressure and common bile duct pressure increased in the 12-wk group(25.19±7.77 mmHg vs 40.56±11.81 mmHg,22.35±7.60 mmHg vs 38.51±11.57mmHg,P<0.05).Serum VIP was significantly elevated in the 6-and 12-wk groups and serum CCK-8 was decreased significantly in the 12-wk group.CONCLUSION:Pigment gallstone-causing diet may induce SO dysfunction.The tension of the SO increased.The disturbance in SO motility may play a role in pigment gallstone formation,and changes in serum VIP and CCK-8 may be important causes of SO dysfunction.     

Effects of sphincter of Oddi motility on the formation of cholesterol gallstones

AIM: To investigate the mechanisms and effects of sphincter of Oddi (SO) motility on cholesterol gallbladder stone formation in guinea pigs.METHODS: Thirty-four adult male Hartley guinea pigs were divided randomly into two groups, the control group (n = 10) and the cholesterol gallstone group (n = 24), which was sequentially divided into four subgroups with six guinea pigs each according to time of sacrifice. The guinea pigs in the cholesterol gallstone group were fed a cholesterol lithogenic diet and sacrificed after 3, 6, 9, and 12 wk. SO manometry and recording of myoelectric activity were obtained by a multifunctional physiograph at each stage. Cholecystokinin-A receptor (CCKAR) expression levels in SO smooth muscle were detected by quantitative real-time PCR (qRT-PCR) and serum vasoactive intestinal peptide (VIP), gastrin, and cholecystokinin octapeptide (CCK-8) were detected by enzyme-linked immunosorbent assay at each stage in the process of cholesterol gallstone formation.RESULTS: The gallstone formation rate was 0%, 0%, 16.7%, and 83.3% in the 3, 6, 9, and 12 wk groups, respectively. The frequency of myoelectric activity in the 9 wk group, the amplitude of myoelectric activity in the 9 and 12 wk groups, and the amplitude and the frequency of SO in the 9 wk group were all significantly decreased compared to the control group. The SO basal pressure and common bile duct pressure increased markedly in the 12 wk group, and the CCKAR expression levels increased in the 6 and 12 wk groups compared to the control group. Serum VIP was elevated significantly in the 9 and 12 wk groups and gastrin decreased significantly in the 3 and 9 wk groups. There was no difference in serum CCK-8 between the groups.CONCLUSION: A cholesterol gallstone-causing diet can induce SO dysfunction. The increasing tension of the SO along with its decreasing activity may play an important role in cholesterol gallstone formation. Expression changes of CCKAR in SO smooth muscle and serum VIP and CCK-8 may be important causes of SO dysfunction.     

双气消滞散对G豚鼠致石后胆囊调宁蛋白的影响

[目的]探讨双气消滞散促进胆管动力的作用机制。[方法]将受试豚鼠随机分为4组,即正常组、模型组、双气消滞散(中药)组、熊去氧胆酸(西药)组。后3组采用高胆固醇致石食饵诱发法建立豚鼠胆结石动物模型,并使其发生继发性胆囊运动功能障碍,其中中药组、西药组分别给予相应药物进行实验性治疗,连续7周后,分别对引起实验性豚鼠胆囊运动功能障碍的胆囊组织调宁蛋白(Cap)表达进行观察。[结果]中药组能有效促进胆囊动力(与模型组比较P<0.01),并且其效果优于西药组(P<0.01)。模型组动物胆囊组织Cap表达水平较正常组显著升高(P<0.01),中药组和西药组胆囊组织Cap表达水平虽均高于正常组(分别P<0.01、<0.05),但与模型组比较,其水平均明显降低(均P<0.01),且中药、西药2组胆囊组织Cap表达水平比较差异无统计学意义(P>0.05)。[结论]双气消滞散能显著促进胆囊动力,其作用机制可能与下调胆囊平滑肌组织Cap水平,提高胆囊平滑肌收缩能力有关。     

Comparison of effects of cholecystokinin and erythromycin on bile chemistry and gallstone formation in aged guinea pigs.

BACKGROUND: There has been considerable interest in gall bladder motility in recent years. We compared the effects of cholecystokinin (CCK) and erythromycin on bile chemistry and gallstone formation in aged guinea pigs. METHODS: Two groups of guinea pigs (1-mo and 3-y old; n=40 each) were studied. Each group was divided into four subgroups of 10 animals each; one subgroup received lithogenic diet, one each received CCK or erythromycin daily in addition to lithogenic diet for 4 weeks, and one received normal diet. After 4 weeks, the presence of gallstones or sludge was recorded and bile composition including concentrations of bile acid, cholesterol, lecithin and protein concentrations was studied. RESULTS: No gallstones were observed in the 1-mo-old animals. In the 3-year-old animals, 9 of 10 guinea pigs on lithogenic diet and 4 of 10 in each treatment subgroup and the normal diet subgroup developed gallstones. CCK and erythromycin had similar effects on bile chemistry and stone formation. CONCLUSIONS: Aging increases the formation of gallstones in guinea pigs. Erythromycin is as effective as CCK in reducing gallstone formation by improving gall bladder motility.     

Endogenous Hypercholecystokininemia,But Not Aspirin,Reduces the Gallstone Incidence in the Hamster Model

Borch K, Chu M, Kullman E, Carlsson B, Rehfeld JF. Endogenous hypercholecystokininemia, but not aspirin, reduces the gallstone incidence in the hamster model. Scand J Gastroenterol 1994;29:740-743.

Background: Studies in humans and rodents indicate that gallstone development may be prevented by inhibiting gallbladder mucus hypersecretion with non-steroidal anti-inflammatory drugs or by preventing stasis of gallbladder bile with administration of cholecystokinin. Methods: The effect of oral aspirin and pancreaticobiliary diversion with endogenous hypercholecystokininemia on crystal and gallstone formation was studied in Syrian golden hamsters fed a lithogenic diet for 8 weeks. Results: None of the control animals fed a normal diet developed gallstones or crystals in gallbladder bile. Gallstones developed in 67% of the animals fed a lithogenic diet only. The gallstone prevalence did not differ significantly in animals on a lithogenic diet and a daily aspirin dose of 6 mg/kg (gallstone prevalence, 60%) or 100 mg/kg (gallstone prevalence, 70%), whereas it was significantly lower in animals with endogenous hypercholecystokininemia on a lithogenic diet (gallstone prevalence, 29%). The prevalence of crystals in gallbladder bile did not differ significantly between any of the experimental groups. Conclusions: It is concluded that in hamsters on a lithogenic diet, aspirin does not prevent gallstone formation, whereas endogenous hypercholecystokininemia reduces the prevalence of stones without affecting the occurrence of crystals in gallbladder bile.     

Cholecystokinin receptor A gene polymorphism in gallstone disease and gallbladder cancer

Background and Aim:  Gallbladder carcinoma (GBC) usually arises in the background of gallstone disease which may be causatively related to decreased gallbladder contractility. Cholecystokinin receptor A ( CCK-AR ) mediates signals resulting in gallbladder contraction. Deteriorating gallbladder contraction promotes gallstone formation. A common genetic polymorphism of CCK-AR may be causatively associated with the risk of gallstone and GBC. This study aimed to understand the association of CCK-AR Pst I polymorphism in gallstone disease with gallbladder cancer.
Method:  This study included 165 gallstone patients, 139 GBC patients, and 190 healthy subjects. Genotyping was done using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method.
Results:  The frequency of the A1A1 genotype of CCK-AR was significantly higher in gallstone patients than healthy individuals ( P  = 0.008 odds ratio [OR] = 2.25, and 95% confidence interval [CI]:1.2–4.1). However, there was a significant difference in the frequency of A1A1 genotype when gallstone patients were compared to GBC patients ( P  = 0.041, OR = 0.49, and 95% CI: 0.3–0.9). On stratification of GBC patients according to presence or absence of gallstones, GBC patients without stones were compared to controls and GBC patients with stones were compared to stone patients; however, no significant differences in frequencies were observed.
Conclusion:  The results suggest that the A1A1 genotype of CCK-AR is an independent genetic risk factor for gallstone disease and does not modulate the susceptibility of gallbladder cancer.     

中药胆宁片治疗胆囊胆固醇结石作用机制的实验研究

[目的]探讨胆宁片对胆固醇结石豚鼠胆汁中黏蛋白及血清IL-2水平的影响.[方法]雌性豚鼠60只,体重（300±20）g,随机分为空白组、模型组、胆宁片组和熊脱氧胆酸组,每组15只;除空白组外,采用“高胆固醇致石食饵诱发法”建立豚鼠胆固醇结石模型,并于造模成功后分别对各治疗组予药物干预,胆宁片组灌服胆宁混悬液0.52 g· kg-1·d-1,熊脱氧胆酸组灌服熊脱氧胆酸混悬液0.05 g·kg-1·d-1,模型组与空白组均灌服等容量的生理盐水,8周后观察各组豚鼠一般情况、胆汁中黏蛋白及血清IL-2水平.[结果]胆宁片可显著降低豚鼠胆固醇结石成石率,并能显著降低胆囊黏蛋白及血清IL-2水平（P＜0.05,P＜0.01）.[结论]胆宁片能直接调节胆囊黏蛋白等相关促成核因子,同时能通过调节血清中IL-2间接调控胆囊黏蛋白水平,从而调控成核过程,对胆囊胆固醇结石有一定的治疗作用.     

Effects of sphingolipid synthesis inhibition on cholesterol gallstone formation in C57BL/6J mice

Background: Sphingolipids play a very important role in cell membrane formation, signal transduction and plasma lipoprotein metabolism. The first rate‐limiting step in the sphingolipid biosynthetic pathway is catalyzed by serine palmitoyltransferase (SPT), and myriocin is a potent and specific inhibitor of SPT. We investigated the impact of SPT inhibition on cholesterol gallstone formation in C57BL/6J mice. Methods: Three groups of eight‐week‐old C57BL/6J mice were utilized. Each group consisted of 20 mice; group A, B, and C were fed normal chow, lithogenic diet with phosphate buffered saline, and lithogenic diet with myriocin (0.3 mg/kg), respectively, for 6 weeks. The ceramide levels in both serum and bile were assessed by high performance liquid chromatography analysis. Protein expression of ERK, JNK and p38 in the extracted gallbladder were determined by Western‐blot analysis. Results: Myriocin treatment caused a significant decrease in the rate of cholesterol gallstone formation. The lithogenic diet mice (group B) showed the highest ceramide activities in both the serum and bile among all the tested groups and there was significant suppression of the ceramide levels in both the serum and bile of the myriocin‐treated mice (group C, p < 0.05). Phosphorylation of p38 in the gallbladder was increased in the lithogenic‐diet mice and the expression of phosphorylated p38 was significantly suppressed in the myriocin treated mice. Conclusions: SPT inhibition by myriocin suppressed gallstone formation and the levels of ceramide in both the serum and bile. p38 in the cellular signaling pathways might be associated with cholesterol gallstone formation.     

Deficiency of Niemann‐Pick C1 protein protects against diet‐induced gallstone formation in mice

Background/aims: Receptor‐mediated endocytosis is a critical cellular mechanism for the uptake of lipoprotein cholesterol in the liver. Because Niemann‐Pick C1 (NPC1) protein is a key component for the intracellular distribution of cholesterol originating from lipoprotein endocytosis, it may play an important role in controlling biliary cholesterol secretion and gallstone formation induced by a lithogenic diet. Methods: We studied biliary cholesterol secretion, gallbladder lipid composition and gallstone formation in NPC1‐deficient mice fed a low‐fat lithogenic diet (1.5% cholesterol and 0.5% cholic acid) compared with control animals under the same diet. Results: The lipid secretion response to the lithogenic diet was impaired in NPC1 (?/?) mice, leading to a decreased cholesterol output and an increased hepatic cholesterol concentration compared with the lithogenic diet‐fed wild‐type mice. A decreased cholesterol saturation index was found in the gallbladder bile of NPC1 (+/?) and (?/?) mice after lithogenic diet feeding. Consequently, mice with a partial or a total deficiency of NPC1 had a drastically lower frequency of gallbladder cholesterol crystals and a reduced prevalence of gallstones. Conclusion: Hepatic NPC1 expression is an important factor for regulating the biliary secretion of diet‐derived cholesterol as well as for diet‐induced cholesterol gallstone formation in mice.