Department of Medicine, Division of Gastroenterology, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, TX 76504, USA.
Am J Physiol Gastrointest Liver Physiol. 2011 Dec;301(6):G981-91. doi: 10.1152/ajpgi.00061.2011. Epub 2011 Sep 8.
Increased cholangiocyte growth is critical for the maintenance of biliary mass during liver injury by bile duct ligation (BDL). Circulating levels of testosterone decline following castration and during cholestasis. Cholangiocytes secrete sex hormones sustaining cholangiocyte growth by autocrine mechanisms. We tested the hypothesis that testosterone is an autocrine trophic factor stimulating biliary growth. The expression of androgen receptor (AR) was determined in liver sections, male cholangiocytes, and cholangiocyte cultures [normal rat intrahepatic cholangiocyte cultures (NRICC)]. Normal or BDL (immediately after surgery) rats were treated with testosterone or antitestosterone antibody or underwent surgical castration (followed by administration of testosterone) for 1 wk. We evaluated testosterone serum levels; intrahepatic bile duct mass (IBDM) in liver sections of female and male rats following the administration of testosterone; and secretin-stimulated cAMP levels and bile secretion. We evaluated the expression of 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3, the enzyme regulating testosterone synthesis) in cholangiocytes. We evaluated the effect of testosterone on the proliferation of NRICC in the absence/presence of flutamide (AR antagonist) and antitestosterone antibody and the expression of 17β-HSD3. Proliferation of NRICC was evaluated following stable knock down of 17β-HSD3. We found that cholangiocytes and NRICC expressed AR. Testosterone serum levels decreased in castrated rats (prevented by the administration of testosterone) and rats receiving antitestosterone antibody. Castration decreased IBDM and secretin-stimulated cAMP levels and ductal secretion of BDL rats. Testosterone increased 17β-HSD3 expression and proliferation in NRICC that was blocked by flutamide and antitestosterone antibody. Knock down of 17β-HSD3 blocks the proliferation of NRICC. Drug targeting of 17β-HSD3 may be important for managing cholangiopathies.
在胆管结扎（BDL）导致的肝损伤过程中，增加胆管细胞生长对于维持胆管质量至关重要。去势和胆汁淤积时，循环中的睾酮水平下降。胆管细胞通过自分泌机制分泌性激素，维持胆管细胞生长。我们检验了睾酮是刺激胆管生长的自分泌营养因子这一假说。我们在肝切片、雄性胆管细胞和胆管细胞培养物（正常大鼠肝内胆管细胞培养物（NRICC））中检测了雄激素受体（AR）的表达。对正常或 BDL（手术后立即）大鼠给予睾酮或抗睾酮抗体治疗，或行手术去势（随后给予睾酮）治疗 1 周。我们评估了睾酮血清水平、女性和男性大鼠给予睾酮后肝内胆管质量（IBDM）；以及促胰液素刺激的 cAMP 水平和胆汁分泌。我们评估了胆管细胞中 17β-羟类固醇脱氢酶 3（17β-HSD3，调节睾酮合成的酶）的表达。我们评估了睾酮对 NRICC 增殖的影响，方法是在缺乏/存在氟他胺（AR 拮抗剂）和抗睾酮抗体的情况下，以及在 17β-HSD3 稳定敲低的情况下。我们发现胆管细胞和 NRICC 表达 AR。去势大鼠（给予睾酮可预防）和接受抗睾酮抗体的大鼠的睾酮血清水平下降。去势降低了 BDL 大鼠的 IBDM 和促胰液素刺激的 cAMP 水平及胆管分泌。睾酮增加了 NRICC 中的 17β-HSD3 表达和增殖，而氟他胺和抗睾酮抗体可阻断其作用。17β-HSD3 的敲低可阻断 NRICC 的增殖。17β-HSD3 的药物靶向治疗对于管理胆管疾病可能很重要。
