Relevance of Niemann-Pick type C1 protein expression in controlling plasma cholesterol and biliary lipid secretion in mice

Authors

  • Ludwig Amigo,

    1. From the Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica, Santiago, Chile
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  • Hegaly Mendoza,

    1. From the Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica, Santiago, Chile
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  • Juan Castro,

    1. From the Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica, Santiago, Chile
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  • Verónica Quiñones,

    1. From the Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica, Santiago, Chile
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  • Juan Francisco Miquel,

    1. From the Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica, Santiago, Chile
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  • Silvana Zanlungo

    Corresponding author
    1. From the Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica, Santiago, Chile
    • Pontificia Universidad Católica de Chile, Departamento de Gastroenterología, Marcoleta 367, Casilla 114-D, Santiago, Chile. fax: (56) 2-639-7780.
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Abstract

Receptor-mediated endocytosis is one of the major mechanisms for uptake of lipoprotein cholesterol in the liver. Because Niemann-Pick C1 (NPC1) protein is a key component in the intracellular distribution of cholesterol obtained from lipoproteins by the endocytic pathway, it may play a critical role in controlling plasma lipoprotein cholesterol and its biliary secretion. A murine model of Niemann-Pick type C disease (NPC), the NPC1-deficient [NPC1 (−/−)] mouse, was used to evaluate the relevance of hepatic NPC1 expression in regulating plasma lipoprotein cholesterol profile and biliary lipid secretion under chow and high-cholesterol diets. Total plasma cholesterol concentrations were increased in NPC1 (−/−) mice compared with wild-type mice when both mouse strains were fed chow or high-cholesterol diets. The increased plasma cholesterol levels found in NPC1 (−/−) mice were mostly due to elevated cholesterol content in larger and more heterogeneous HDL particles. On the chow diet, biliary lipid secretion was not impaired by NPC1 deficiency. Furthermore, chow-fed NPC1 (−/−) mice showed a small, but significant, increase in biliary cholesterol secretion. On the high-cholesterol diet, wild-type mice increased biliary cholesterol output, whereas NPC1 (−/−) mice did not. Finally, hepatic NPC1 overexpression by adenovirus-mediated gene transfer increased biliary cholesterol secretion by 100% to 150% in both wild-type mice and cholesterol-fed NPC1 (−/−) mice. In conclusion, hepatic NPC1 expression is an important factor for regulating plasma HDL cholesterol levels and biliary cholesterol secretion in mice.

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