Gender Differences in Cholesterol Nucleation in Native Bile: Estrogen Is a Potential Contributory Factor

The incidence of gallstone disease is two to three times higher in women than in men, and female sex hormones, particularly estrogens, have been implicated as contributory factors. Cholesterol nucleation is the initial step in gallstone pathogenesis and proceeds from cholesterol-rich phospholipid vesicles. The aim of this study was to investigate if there is a difference in cholesterol nucleation rates in male and female bile and whether estrogen influences nucleation rates by interacting with cholesterol-rich regions known as “lipid rafts” that exist within the cholesterol-phospholipid vesicles of the bile. Cholesterol nucleation from native prairie dog bile and the interaction of estrogens with lipid rafts in model bile solutions were investigated using Förster resonance energy transfer (FRET). Female native bile samples showed a greater reduction in energy transfer than did male native bile, indicating that cholesterol nucleation occurred more readily in female bile than in male bile. Model bile experiments demonstrated that the addition of estrogen has a significant effect, either cholesterol nucleation or raft disruption, but only in samples containing cholesterol-rich rafts. These results suggest that estrogen interacts with cholesterol-rich rafts in vesicles within bile to promote cholesterol nucleation and predispose females to gallstone formation.

胆结石疾病在女性中的发病率比男性高两到三倍，并且女性性激素，尤其是雌激素，被认为是致病因素。胆固醇成核是胆结石发病机制中的起始步骤，源于富含胆固醇的磷脂囊泡。本研究的目的是调查男性和女性胆汁中胆固醇成核速率是否存在差异，以及雌激素是否通过与胆汁中胆固醇 - 磷脂囊泡内被称为“脂筏”的富含胆固醇区域相互作用来影响成核速率。利用福斯特共振能量转移（FRET）研究了来自草原犬鼠天然胆汁的胆固醇成核以及雌激素与模拟胆汁溶液中脂筏的相互作用。女性天然胆汁样本比男性天然胆汁样本显示出更大的能量转移降低，表明胆固醇在女性胆汁中比在男性胆汁中更容易成核。模拟胆汁实验表明，添加雌激素具有显著影响，无论是对胆固醇成核还是脂筏破坏，但仅在含有富含胆固醇脂筏的样本中。这些结果表明，雌激素与胆汁内囊泡中富含胆固醇的脂筏相互作用，促进胆固醇成核，并使女性更易形成胆结石。