Jiangsu Institute for Food and Drug Control, Nanjing 210019, China.
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Phytomedicine. 2022 Jul;101:154120. doi: 10.1016/j.phymed.2022.154120. Epub 2022 Apr 20.
Postmenopausal women have a high incidence of atherosclerosis. Phytosterols have been shown to have cholesterol-lowering properties. Alisa B 23-acetate (AB23A) is a biologically active plant sterol isolated from Chinese herbal medicine Alisma. However, the atherosclerosis effect of AB23A after menopause and its possible mechanism have not been reported yet.
To explore whether AB23A can prevent atherosclerosis by regulating farnesoid X receptor and subsequently increasing fecal bile acid and cholesterol excretion to reduce plasma cholesterol levels.
Aortic samples from premenopausal and postmenopausal women with ascending aortic arteriosclerosis were analyzed, and bilateral ovariectomized (OVX) female LDLR mice and free fatty acid (FFA)-treated L02 cells were used to analyze the effect of AB23A supplementation therapy.
AB23A increased fecal cholesterol and bile acids (BAs) excretion dependent on activation of hepatic farnesoid X receptor (FXR) in ovariectomized mice. AB23A inhibited hepatic cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1) via inducing small heterodimer partner (SHP) expression. On the other hand, AB23A increased the level of hepatic chenodeoxycholic acid (CDCA), and activated the hepatic BSEP signaling. The activation of hepatic FXR-BSEP signaling by AB23A in ovariectomized mice was accompanied by the reduction of liver cholesterol, hepatic lipolysis, and bile acids efflux, and reduced the damage of atherosclerosis. In vitro, AB23A fixed abnormal lipid metabolism in L02 cells and increased the expression of FXR, BSEP and SHP. Moreover, the inhibition and silencing of FXR canceled the regulation of BSEP by AB23A in L02 cells.
Our results shed light into the mechanisms behind the cholesterol-lowering of AB23A, and increasing FXR-BSEP signaling by AB23A may be a potential postmenopausal atherosclerosis therapy.
绝经后妇女的动脉粥样硬化发病率很高。植物甾醇已被证明具有降低胆固醇的特性。Alisa B 23- 乙酸酯（AB23A）是一种从中药泽泻中分离得到的具有生物活性的植物甾醇。然而，AB23A 绝经后对动脉粥样硬化的作用及其可能的机制尚未报道。
探讨 AB23A 是否可以通过调节法尼醇 X 受体（FXR），进而增加粪便胆汁酸和胆固醇排泄，降低血浆胆固醇水平，从而预防动脉粥样硬化。
分析绝经前和绝经后升主动脉粥样硬化妇女的主动脉样本，并使用双侧卵巢切除（OVX）雌性 LDLR 小鼠和游离脂肪酸（FFA）处理的 L02 细胞来分析 AB23A 补充治疗的效果。
AB23A 增加了粪便胆固醇和胆汁酸（BAs）的排泄，这依赖于 OVX 小鼠中肝 FXR 的激活。AB23A 通过诱导小异二聚体伴侣（SHP）表达来抑制肝胆固醇 7α-羟化酶（CYP7A1）和甾醇 12α-羟化酶（CYP8B1）。另一方面，AB23A 增加了肝鹅脱氧胆酸（CDCA）的水平，并激活了肝 BSEP 信号。AB23A 在 OVX 小鼠中激活肝 FXR-BSEP 信号伴随着肝脏胆固醇的减少、肝脂肪分解和胆汁酸外排的增加，以及动脉粥样硬化损伤的减少。在体外，AB23A 固定了 L02 细胞中异常的脂质代谢，并增加了 FXR、BSEP 和 SHP 的表达。此外，FXR 的抑制和沉默消除了 AB23A 在 L02 细胞中对 BSEP 的调节。
我们的结果揭示了 AB23A 降低胆固醇的机制，AB23A 增加 FXR-BSEP 信号可能是绝经后动脉粥样硬化治疗的一种潜在方法。
