Abstract
Monogenic familial hypercholesterolemia is characterized by impaired cellular uptake of apolipoprotein B containing lipoproteins. However, its consequences on whole-body cholesterol metabolism are unclear. We investigated cholesterol metabolism in wild-type mice (control) and in knockout (KO) mice for the low-density lipoprotein receptor (LDLR-KO) and for apolipoprotein E (apoE-KO) containing the genetic basis of the C57BL/6J mice, under a cholesterol-free diet. Cholesterol and “non-cholesterol” sterols (cholestanol, desmosterol, and lathosterol) were measured in plasma, tissues, as well as in feces as cholesterol and its bacterial modified products (neutral sterols) using gas chromatography/mass spectrometry, and bile acids were measured by an enzymatic method. Compared to controls, LDLR-KO mice have elevated plasma and whole-body cholesterol concentrations, but total fecal sterols are not modified, characterizing unaltered body cholesterol synthesis together with impaired body cholesterol excretion. ApoE-KO mice presented the highest concentrations of plasma cholesterol, whole-body cholesterol, cholestanol, total fecal sterols, and cholestanol, compatible with high cholesterol synthesis rate; the latter seems attributed to elevated body desmosterol (Bloch cholesterol synthesis pathway). Nonetheless, whole-body lathosterol (Kandutsch-Russel cholesterol synthesis pathway) decreased in both KO models, likely explaining the diminished fecal bile acids. We have demonstrated for the first time quantitative changes of cholesterol metabolism in experimental mouse models that explain differences between LDLR-KO and apoE-KO mice. These findings contribute to elucidate the metabolism of cholesterol in human hypercholesterolemia of genetic origin.
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Acknowledgements
The authors express their gratitude to Mr. Antônio dos Santos (Centro de Manutenção e Experimentação de Animais da Clínica Médica, Disciplina de Reumatologia FMUSP) for providing animal care, Mrs. Rosana Aparecida Manólio Soares Freitas (Laboratory of Functional Food, Departamento de Nutrição, USP) for support with the bile acid analyses, and Monique de Fátima Mello and Francisca Elda Batista (Laboratório de Lipides, LIM-10, HCFMUSP) for their technical support.
Funding
This work was supported by the São Paulo Research Foundation (FAPESP), São Paulo, Brazil (grant number: 2015-17566-2).
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All procedures were approved by the Animal Use Ethics Committee of the Faculdade de Medicina FMUSP, Universidade de Sao Paulo (protocol number 194/15) and were conducted in accordance with the guidelines of the National Institutes of Health (NIH; USA), the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Research, 1996), and the Ethical Principles in Animal Experimentation adopted by the Brazilian Society of Animal Sciences Laboratory (SBCAL). Conflict of interest
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Key points
• ApoE-KO mice synthesize more cholesterol than LDLR-KO and control mice.
• Cholesterol synthesis was elevated by desmosterol and decreased by lathosterol.
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Nunes, V.S., Cazita, P.M., Catanozi, S. et al. Cholesterol metabolism in mice models of genetic hypercholesterolemia. J Physiol Biochem 76, 437–443 (2020). https://doi.org/10.1007/s13105-020-00753-1
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DOI: https://doi.org/10.1007/s13105-020-00753-1