TY - JOUR
T1 - Relevance of Niemann-Pick type C1 protein expression in controlling plasma cholesterol and biliary lipid secretion in mice
AU - Amigo, Ludwig
AU - Mendoza, Hegaly
AU - Castro, Juan
AU - Quiones, Verónica
AU - Miquel, Juan Francisco
AU - Zanlungo, Silvana
N1 - Funding Information:
Abbreviations: NPC, Niemann-Pick type C; LDL, low-density lipoprotein; NPC1, Niemann-Pick C1 protein; CM, chylomicron; HDL, high-density lipoprotein; VLDL, very low-density lipoprotein; SR-BI, Scavenger receptor class B type-I; NPC1 (−/−) mice, BALB/c NPC1-deficient mice; wild-type mice, BALB/c control wild-type mice; FPLC, fast-performance liquid chromatography; apo, apolipoprotein; ABC, ATP-binding cassette; LDLR, LDL receptor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; bw, body weight; IDL, intermediate-density lipoprotein. From the Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica, Santiago, Chile. Received December 11, 2001; accepted June 27, 2002. Supported by Fondo Nacional de Desarrollo Científico y Tecnológico (FON-DECYT, Grant 1000567). Address reprint requests to: Silvana Zanlungo, Ph.D., Pontificia Universidad Católica de Chile, Departamento de Gastroenterología, Marcoleta 367, Casilla 114-D, Santiago, Chile. E-mail: [email protected]; fax: (56) 2-639-7780. Copyright © 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3604-0007$35.00/0 doi:10.1053/jhep.2002.35617
PY - 2002/10/1
Y1 - 2002/10/1
N2 - 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 (-1-) mice. In conclusion, hepatic NPC1 expression is an important factor for regulating plasma HDL cholesterol levels and biliary cholesterol secretion in mice.
AB - 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 (-1-) mice. In conclusion, hepatic NPC1 expression is an important factor for regulating plasma HDL cholesterol levels and biliary cholesterol secretion in mice.
UR - http://www.scopus.com/inward/record.url?scp=0036789434&partnerID=8YFLogxK
U2 - 10.1016/S0270-9139(02)00088-5
DO - 10.1016/S0270-9139(02)00088-5
M3 - Article
C2 - 12297829
AN - SCOPUS:0036789434
VL - 36
SP - 819
EP - 828
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 4 I
ER -