TY - JOUR
T1 - Transgenic overexpression of Niemann-Pick C2 protein promotes cholesterol gallstone formation in mice
AU - Acuña, Mariana
AU - González-Hódar, Lila
AU - Amigo, Ludwig
AU - Castro, Juan
AU - Morales, M. Gabriela
AU - Cancino, Gonzalo I.
AU - Groen, Albert K.
AU - Young, Juan
AU - Miquel, Juan Francisco
AU - Zanlungo, Silvana
N1 - Funding Information:
This study was supported by grants from the Fondo Nacional de Desarrollo Científico y Tecnológico ( FONDECYT ) (grant numbers 1070622 and 1110310 to SZ, and 1130303 to JFM); Fondo Nacional de Desarrollo de Areas Prioritarias, FONDAP , Project no. 15090007 , Center for Genome Regulation ( CGR ) to SZ and JFM; Comisión Nacional de ciencia y tecnología ( CONICYT ) PhD student grant # 21120490 to MA.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - Background & Aims Niemann-Pick C2 (NPC2) is a lysosomal protein involved in the egress of low-density lipoprotein-derived cholesterol from lysosomes to other intracellular compartments. NPC2 has been detected in several tissues and is also secreted from the liver into bile. We have previously shown that NPC2-deficient mice fed a lithogenic diet showed reduced biliary cholesterol secretion as well as cholesterol crystal and gallstone formation. This study aimed to investigate the consequences of NPC2 hepatic overexpression on liver cholesterol metabolism, biliary lipid secretion, gallstone formation and the effect of NPC2 on cholesterol crystallization in model bile. Methods We generated NPC2 transgenic mice (Npc2.Tg) and fed them either chow or lithogenic diets. We studied liver cholesterol metabolism, biliary lipid secretion, bile acid composition and gallstone formation. We performed cholesterol crystallization studies in model bile using a recombinant NPC2 protein. Results No differences were observed in biliary cholesterol content or secretion between wild-type and Npc2.Tg mice fed the chow or lithogenic diets. Interestingly, Npc2.Tg mice showed an increased susceptibility to the lithogenic diet, developing more cholesterol gallstones at early times, but did not show differences in the bile acid hydrophobicity and gallbladder cholesterol saturation indices compared to wild-type mice. Finally, recombinant NPC2 decreased nucleation time in model bile. Conclusions These results suggest that NPC2 promotes cholesterol gallstone formation by decreasing the cholesterol nucleation time, indicating a pro-nucleating function of NPC2 in bile.
AB - Background & Aims Niemann-Pick C2 (NPC2) is a lysosomal protein involved in the egress of low-density lipoprotein-derived cholesterol from lysosomes to other intracellular compartments. NPC2 has been detected in several tissues and is also secreted from the liver into bile. We have previously shown that NPC2-deficient mice fed a lithogenic diet showed reduced biliary cholesterol secretion as well as cholesterol crystal and gallstone formation. This study aimed to investigate the consequences of NPC2 hepatic overexpression on liver cholesterol metabolism, biliary lipid secretion, gallstone formation and the effect of NPC2 on cholesterol crystallization in model bile. Methods We generated NPC2 transgenic mice (Npc2.Tg) and fed them either chow or lithogenic diets. We studied liver cholesterol metabolism, biliary lipid secretion, bile acid composition and gallstone formation. We performed cholesterol crystallization studies in model bile using a recombinant NPC2 protein. Results No differences were observed in biliary cholesterol content or secretion between wild-type and Npc2.Tg mice fed the chow or lithogenic diets. Interestingly, Npc2.Tg mice showed an increased susceptibility to the lithogenic diet, developing more cholesterol gallstones at early times, but did not show differences in the bile acid hydrophobicity and gallbladder cholesterol saturation indices compared to wild-type mice. Finally, recombinant NPC2 decreased nucleation time in model bile. Conclusions These results suggest that NPC2 promotes cholesterol gallstone formation by decreasing the cholesterol nucleation time, indicating a pro-nucleating function of NPC2 in bile.
KW - Gallbladder
KW - Lithiasis
KW - Lithogenic diet
KW - NPC2
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U2 - 10.1016/j.jhep.2015.10.002
DO - 10.1016/j.jhep.2015.10.002
M3 - Article
C2 - 26453970
AN - SCOPUS:84954286186
VL - 64
SP - 361
EP - 369
JO - Journal of Hepatology
JF - Journal of Hepatology
SN - 0168-8278
IS - 2
ER -