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Updated: May 11, 2025
Assessing Whole-Body Lipid-Handling Capacity in Mice
Published on: November 24, 2020
Ablation of Mouse Selenium-Binding Protein 1 and 2 Elevates LDL by Disruption of Cholesterol Efflux and Lipid
Shuangli Zhao1, Yingxia Song1, Yuko Nakashima1
1Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Abstract:
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 SeBP1 and SeBP2 double-knockout mice (SeBP1/2-DK). SeBP1/2 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.
Insights
Selenium-binding proteins 1 and 2 (SeBP1/2) play crucial roles in liver lipid metabolism. Deleting these proteins impairs fatty acid oxidation and cholesterol efflux, offering new therapeutic targets for lipid disorders.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Selenium-binding protein 1 (SeBP1) is known for anticancer properties and impacts kidney lipid metabolism via the PPARA pathway.
- The liver's physiological role of SeBP1 is unclear due to the presence of the similar SeBP2.
- Investigating SeBP1 and SeBP2 function in the liver is essential for understanding lipid metabolism.
Purpose of the Study:
- To elucidate the roles of SeBP1 and SeBP2 in hepatic lipid metabolism.
- To investigate the impact of SeBP1/2 deletion on fatty acid and cholesterol pathways in the liver.
- To explore the regulatory effects of SeBP1 on PPARA and related genes.
Main Methods:
- Generation and analysis of SeBP1/2 double-knockout (DK) mice.
- Gene expression analysis related to hepatic lipid metabolism.
- Cellular studies involving HepG2 cells transfected with human SeBP1 (hSeBP1).
- Measurement of serum lipid profiles (LDL, HDL, triglycerides).
Main Results:
- SeBP1/2 deletion in mice did not cause significant phenotypic changes but inhibited hepatic fatty acid oxidation and cholesterol efflux.
- Overexpression of hSeBP1 in HepG2 cells upregulated PPARA and its target genes, reducing non-esterified fatty acids.
- Significant differences in serum LDL, HDL, and triglyceride levels were observed between experimental groups.
Conclusions:
- SeBP1 and SeBP2 are involved in regulating fatty acid oxidation and hepatic cholesterol efflux.
- SeBP1 positively influences the PPARA pathway, impacting lipid metabolism.
- These findings suggest potential therapeutic strategies for managing lipid metabolism disorders.
