Wu Jun, Liu Jie, Waalkes Michael P, Cheng Ming-Liang, Li Ling, Li Cheng-Xiu, Yang Qing
Guiyang Medical College, 550004 Guiyang, China.
Exp Biol Med (Maywood). 2008 Mar;233(3):377-84. doi: 10.3181/0710-RM-269.
Many factors could potentially affect the process of arsenic-induced liver fibrosis. The present study was undertaken to examine the effect of high fat diet on arsenic-induced liver fibrosis and preneoplastic changes. Mice were given sodium arsenite (As3+, 200 ppm) or sodium arsenate (As5+, 200 ppm) in the drinking water for 10 months, and provided a normal diet or a diet containing 20% added fat. Serum aspartate aminotransferase (AST), indicative of liver injury, was elevated in both arsenite and arsenate groups, and a high fat diet further increased these levels. Histopathology (H&E and Masson stain) showed that liver inflammation, steatosis (fatty liver), hepatocyte degeneration, and fibrosis occurred with arsenic alone, but their severity was markedly increased with the high fat diet. Total liver RNA was isolated for real-time RT-PCR analysis. Arsenic exposure increased the expression of inflammation genes, such as TNF-alpha, IL-6, iNOS, chemokines, and macrophage inflammatory protein-2. The expression of the stress-related gene heme oxygenase-1 was increased, while metallothionein-1 and GSH S-transferase-pi were decreased when arsenic was combined with the high fat diet. Expression of genes related to liver fibrosis, such as procollagen-1 and -3, SM-actin and TGF-beta, were synergistically increased in the arsenic plus high fat diet group. The expression of genes encoding matrix metalloproteinases (MMP2, MMP9) and tissue inhibitors of metalloproteinases (TIMP1, TIMP2) was also enhanced, suggestive of early oncogenic events. In general, arsenite produced more pronounced effects than arsenate. In summary, chronic inorganic arsenic exposure in mice produces liver injury, and a high fat diet markedly increases arsenic-induced hepatofibrogenesis.
许多因素可能会潜在地影响砷诱导的肝纤维化进程。本研究旨在探讨高脂饮食对砷诱导的肝纤维化及癌前病变的影响。给小鼠饮用含亚砷酸钠（As3+，200 ppm）或砷酸钠（As5+，200 ppm）的水10个月，并给予正常饮食或含20%添加脂肪的饮食。指示肝损伤的血清天冬氨酸氨基转移酶（AST）在亚砷酸盐和砷酸盐组中均升高，高脂饮食进一步提高了这些水平。组织病理学（苏木精-伊红染色和马松染色）显示，单独使用砷时会出现肝脏炎症、脂肪变性（脂肪肝）、肝细胞变性和纤维化，但高脂饮食会使它们的严重程度显著增加。分离肝脏总RNA用于实时逆转录-聚合酶链反应分析。砷暴露增加了炎症基因的表达，如肿瘤坏死因子-α、白细胞介素-6、诱导型一氧化氮合酶、趋化因子和巨噬细胞炎性蛋白-2。当砷与高脂饮食联合时，应激相关基因血红素加氧酶-1的表达增加，而金属硫蛋白-1和谷胱甘肽S-转移酶-pi的表达降低。在砷加高脂饮食组中，与肝纤维化相关的基因，如I型和III型前胶原、平滑肌肌动蛋白和转化生长因子-β的表达协同增加。编码基质金属蛋白酶（MMP2、MMP9）和金属蛋白酶组织抑制剂（TIMP1、TIMP2）的基因表达也增强，提示早期致癌事件。一般来说，亚砷酸盐比砷酸盐产生的影响更明显。总之，小鼠长期暴露于无机砷会导致肝损伤，高脂饮食会显著增加砷诱导的肝纤维化。
