Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands.
Departments of Pediatrics and Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands.
J Endocrinol. 2019 Aug;242(2):1-12. doi: 10.1530/JOE-19-0079.
Chronic glucocorticoid overexposure predisposes to the development of atherosclerotic cardiovascular disease in humans. Cholestatic liver disease is associated with increased plasma glucocorticoid levels. Here, we determined - in a preclinical setting - whether the chronic presence of cholestatic liver disease also induces a concomitant negative impact on atherosclerosis susceptibility. Hereto, regular chow diet-fed atherosclerosis-susceptible hypercholesterolemic apolipoprotein E (APOE)-knockout mice were treated with the bile duct toxicant alpha-naphthylisothiocyanate (ANIT) for 8 weeks. ANIT exposure induced the development of fibrotic cholestatic liver disease as evident from collagen deposits and compensatory bile duct hyperproliferation within the liver and the rise in plasma levels of bilirubin (+60%; P < 0.01) and bile acids (10-fold higher; P < 0.01). Adrenal weights (+22%; P < 0.01) and plasma corticosterone levels (+72%; P < 0.01) were increased in ANIT-treated mice. In contrast, atherosclerosis susceptibility was not increased in response to ANIT feeding, despite the concomitant increase in plasma free cholesterol (+30%; P < 0.01) and cholesteryl ester (+42%; P < 0.001) levels. The ANIT-induced hypercorticosteronemia coincided with marked immunosuppression as judged from the 50% reduction (P < 0.001) in circulating lymphocyte numbers. However, hepatic glucocorticoid signaling was not enhanced after ANIT treatment. It thus appears that the immunosuppressive effect of glucocorticoids is uncoupled from their metabolic effect under cholestatic disease conditions. In conclusion, we have shown that cholestatic liver disease-associated endogenous glucocorticoid overexposure does not increase atherosclerosis susceptibility in APOE-knockout mice. Our studies provide novel preclinical evidence for the observations that the hypercholesterolemia seen in cholestatic human subjects does not translate into a higher risk for atherosclerotic cardiovascular disease.
慢性糖皮质激素过度暴露会使人类易患动脉粥样硬化性心血管疾病。胆汁淤积性肝病与血浆糖皮质激素水平升高有关。在这里，我们在临床前环境中确定了慢性胆汁淤积性肝病是否也会对动脉粥样硬化易感性产生相应的负面影响。为此，我们用胆汁毒素 α-萘基异硫氰酸酯 (ANIT) 对易患动脉粥样硬化的高胆固醇血症载脂蛋白 E (APOE)-基因敲除小鼠进行了 8 周的常规饮食喂养。ANIT 暴露诱导了纤维性胆汁淤积性肝病的发展，这从肝内胶原沉积和代偿性胆管增生以及血浆胆红素水平的升高（+60%；P < 0.01）和胆汁酸（升高 10 倍；P < 0.01）中可以看出。ANIT 处理的小鼠肾上腺重量（+22%；P < 0.01）和血浆皮质酮水平（+72%；P < 0.01）升高。尽管血浆游离胆固醇（+30%；P < 0.01）和胆固醇酯（+42%；P < 0.001）水平同时升高，但 ANIT 喂养并未导致动脉粥样硬化易感性增加。ANIT 诱导的高皮质酮血症与明显的免疫抑制同时发生，这可以从循环淋巴细胞数量减少 50%（P < 0.001）来判断。然而，ANIT 治疗后肝内糖皮质激素信号没有增强。因此，似乎在胆汁淤积性疾病条件下，糖皮质激素的免疫抑制作用与其代谢作用脱钩。总之，我们的研究表明，与胆汁淤积性肝病相关的内源性糖皮质激素过度暴露不会增加 APOE 基因敲除小鼠的动脉粥样硬化易感性。我们的研究为以下观察结果提供了新的临床前证据，即在胆汁淤积性人类患者中观察到的高胆固醇血症不会增加动脉粥样硬化性心血管疾病的风险。
