School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
College of Pharmacy, Dankook University, Cheonan 31116, Korea.
Int J Mol Sci. 2019 Jul 29;20(15):3709. doi: 10.3390/ijms20153709.
Hepatic fibrosis is characterized by persistent deposition of extracellular matrix proteins and occurs in chronic liver diseases. The aim of the present study is to investigate whether estrogen deficiency (ED) potentiates hepatic fibrosis in a thioacetamide (TAA)-treated rat model. Fibrosis was induced via intraperitoneal injection (i.p.) of TAA (150 mg/kg/day) for four weeks in ovariectomized (OVX) female, sham-operated female, or male rats. In TAA-treated OVX rats, the activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and γ-glutamyl transferase (GGT) were significantly increased compared to those in TAA-treated sham-operated OVX rats or TAA-treated male rats. Furthermore, α-smooth muscle actin (α-SMA) expression was significantly increased compared to that in TAA-treated sham-operated rats. This was accompanied by the appearance of fibrosis biomarkers including vimentin, collagen-I, and hydroxyproline, in the liver of TAA-treated OVX rats. In addition, ED markedly reduced total glutathione (GSH) levels, as well as catalase (CAT) and superoxide dismutase (SOD) activity in TAA-treated OVX rats. In contrast, hepatic malondialdehyde (MDA) levels were elevated in TAA-treated OVX rats. Apoptosis significantly increased in TAA-treated OVX rats, as reflected by elevated p53, Bcl-2, and cleaved caspase 3 levels. Significant increases in interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) concentrations were exhibited in TAA-treated OVX rats, and this further aggravated fibrosis through the transforming growth factor-β (TGF-β)/Smad pathway. Our data suggest that ED potentiates TAA-induced oxidative damage in the liver, suggesting that ED may enhance the severity of hepatic fibrosis in menopausal women.
肝纤维化的特征是细胞外基质蛋白的持续沉积，并发生在慢性肝病中。本研究旨在探讨雌激素缺乏（ED）是否会加剧硫代乙酰胺（TAA）处理的大鼠模型中的肝纤维化。通过腹腔注射（i.p.）TAA（150mg/kg/天），在去卵巢（OVX）雌性、假手术雌性或雄性大鼠中诱导纤维化 4 周。与 TAA 处理的假手术 OVX 大鼠或 TAA 处理的雄性大鼠相比，TAA 处理的 OVX 大鼠血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、碱性磷酸酶（ALP）和γ-谷氨酰转肽酶（GGT）的活性显著增加。此外，与 TAA 处理的假手术大鼠相比，α-平滑肌肌动蛋白（α-SMA）的表达显著增加。这伴随着纤维化生物标志物的出现，包括 TAA 处理的 OVX 大鼠肝脏中的波形蛋白、胶原-I 和羟脯氨酸。此外，ED 明显降低 TAA 处理的 OVX 大鼠的总谷胱甘肽（GSH）水平以及过氧化氢酶（CAT）和超氧化物歧化酶（SOD）的活性。相反，TAA 处理的 OVX 大鼠肝脏中的丙二醛（MDA）水平升高。TAA 处理的 OVX 大鼠中凋亡明显增加，反映在 p53、Bcl-2 和 cleaved caspase 3 水平升高。TAA 处理的 OVX 大鼠中白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）浓度显著升高，通过转化生长因子-β（TGF-β）/Smad 途径进一步加重纤维化。我们的数据表明，ED 加剧了 TAA 诱导的肝脏氧化损伤，提示 ED 可能加重绝经后妇女的肝纤维化严重程度。
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