São Paulo State University (UNESP), Biosciences Institute, Department of Structural and Functional Biology, Botucatu, SP, Brazil.
São Paulo State University (UNESP), Medical School, Department of Pathology, Botucatu, SP, Brazil.
J Steroid Biochem Mol Biol. 2022 Jan;215:106022. doi: 10.1016/j.jsbmb.2021.106022. Epub 2021 Nov 10.
Vitamin D (VD) deficiency has been associated with increased risk for cirrhosis and hepatocellular carcinoma, a highly incident malignant neoplasia worldwide. On the other hand, VD supplementation has shown some beneficial effects in clinical studies and rodent models of chronic liver disease. However, preventive effects of dietary VD supplementation in cirrhosis-associated hepatocarcinogenesis is still unknow. To investigate this purpose, male Wistar rats submitted to a combined diethylnitrosamine- and thioacetamide-induced model were concomitantly supplemented with VD (5,000 and 10,000 IU/kg diet) for 25 weeks. Liver samples were collected for histological, biochemical and molecular analysis. Serum samples were used to measure 25-hydroxyvitamin D [25(OH)D] and alanine aminotransferase levels. Both VD interventions decreased hepatic collagen deposition and pro-inflammatory p65 protein levels, while increased hepatic antioxidant catalase and glutathione peroxidase activities and serum 25(OH)D, without a clear dose-response effect. Nonetheless, only the highest concentration of VD increased hepatic protein levels of VD receptor, while decreased the number of large preneoplastic glutathione-S-transferase- (>0.5 mm²) and keratin 8/18-positive lesions, as well the multiplicity of hepatocellular adenomas. Moreover, this intervention increased hepatic antioxidant Nrf2 protein levels and glutathione-S-transferase activity. In summary, dietary VD supplementation - in special the highest intervention - showed antifibrotic and antineoplastic properties in chemically-induced cirrhosis-associated hepatocarcinogenesis. The positive modulation of Nrf2 antioxidant axis may be mechanistically involved with these beneficial effects, and may guide future clinical studies.
维生素 D（VD）缺乏与肝硬化和肝细胞癌的风险增加有关，这是一种在全球范围内发生率很高的恶性肿瘤。另一方面，VD 补充剂在慢性肝病的临床研究和啮齿动物模型中显示出一些有益的效果。然而，膳食 VD 补充剂在肝硬化相关肝癌发生中的预防作用尚不清楚。为了研究这一目的，雄性 Wistar 大鼠接受了二乙基亚硝胺和硫代乙酰胺联合诱导的模型，并同时补充 VD（5000 和 10000 IU/kg 饮食）25 周。收集肝组织样本进行组织学、生化和分子分析。采集血清样本用于测量 25-羟维生素 D [25(OH)D]和丙氨酸氨基转移酶水平。两种 VD 干预措施均减少了肝胶原沉积和促炎 p65 蛋白水平，同时增加了肝抗氧化酶过氧化氢酶和谷胱甘肽过氧化物酶的活性和血清 25(OH)D，没有明显的剂量反应效应。尽管如此，只有最高浓度的 VD 增加了肝维生素 D 受体的蛋白水平，同时减少了大的肿瘤前谷胱甘肽-S-转移酶 (>0.5mm²)和角蛋白 8/18 阳性病变的数量，以及肝细胞腺瘤的多发性。此外，这种干预增加了肝抗氧化 Nrf2 蛋白水平和谷胱甘肽-S-转移酶活性。总之，膳食 VD 补充剂 - 特别是最高干预剂量 - 在化学诱导的肝硬化相关肝癌发生中表现出抗纤维化和抗肿瘤特性。Nrf2 抗氧化轴的正向调节可能是这些有益作用的机制之一，并可能指导未来的临床研究。
