Zhao Shuangli, Song Yingxia, Nakashima Yuko, Zou Xing, Koga Takayuki, Ishida Takumi, Li Renshi, Hirota Yuko, Tanaka Yoshitaka, Ishii Yuji
Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Laboratory of Hygienic Chemistry, Daiichi University of Pharmacy, Fukuoka 815-8511, Japan.
Int J Mol Sci. 2025 Apr 3;26(7):3363. doi: 10.3390/ijms26073363.
Selenium-binding protein 1 (SeBP1) is an anticancer factor that affects lipid metabolism in mouse kidneys via the peroxisome proliferator-activated receptor-alpha (PPARA) pathway. However, its physiological role in the liver is difficult to explain because of the presence of the highly homologous selenium-binding protein 2 (SeBP2). To investigate the role of these proteins in the liver, we generated and double-knockout mice (-DK). deletion did not significantly alter the mice phenotypic compared to that of the wild-type strain. Then, we identified the genes involved in hepatic lipid metabolism. The double knockout did not affect fatty acid and cholesterol synthesis, but inhibited fatty acid oxidation and cholesterol efflux. Furthermore, transfection of HepG2 cells with human selenium-binding protein 1 (hSeBP1) positively regulated PPARA and the genes controlled by it. Overexpression of hSeBP1 reduced the levels of non-esterified fatty acids in the culture medium. The serum levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides were significantly different among the three groups. In summary, we elucidated the potential signaling pathways of SeBP1 and SeBP2 in fatty acid oxidation and hepatic cholesterol efflux. Our findings provide insights relevant for developing new strategies to prevent and treat lipid metabolism disorders.
硒结合蛋白1（SeBP1）是一种抗癌因子，它通过过氧化物酶体增殖物激活受体α（PPARA）途径影响小鼠肾脏的脂质代谢。然而，由于高度同源的硒结合蛋白2（SeBP2）的存在，其在肝脏中的生理作用难以解释。为了研究这些蛋白在肝脏中的作用，我们构建了SeBP1和SeBP2双敲除小鼠（SeBP1/2-DK）。与野生型品系相比，SeBP1缺失并未显著改变小鼠的表型。然后，我们鉴定了参与肝脏脂质代谢的基因。双敲除不影响脂肪酸和胆固醇的合成，但抑制脂肪酸氧化和胆固醇流出。此外，用人硒结合蛋白1（hSeBP1）转染HepG2细胞可正向调节PPARA及其控制的基因。hSeBP1的过表达降低了培养基中非酯化脂肪酸的水平。三组之间低密度脂蛋白胆固醇、高密度脂蛋白胆固醇和甘油三酯的血清水平存在显著差异。总之，我们阐明了SeBP1和SeBP2在脂肪酸氧化和肝脏胆固醇流出中的潜在信号通路。我们的研究结果为开发预防和治疗脂质代谢紊乱的新策略提供了相关见解。
