Transgenic overexpression of Niemann-Pick C2 protein promotes cholesterol gallstone formation in mice

详细信息    查看全文

• 作者：Mariana Acuñ ; a¹ ; ⁵ ; ^&dagger ; ; Lila Gonzá ; lez-Hó ; dar¹ ; ^&dagger ; ; Ludwig Amigo¹ ; Juan Castro¹ ; M. Gabriela Morales¹ ; Gonzalo I. Cancino² ; Albert K. Groen³ ; Juan Young⁴ ; Juan Francisco Miquel¹ ; ⁵ ; Silvana Zanlungo¹ ; ⁵ ; ^{silvana@med.puc.cl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：NPC2 ; Niemann-Pick C2 ; NPC1 ; Niemann-Pick C1 ; NPC2(h/h) ; Niemann-Pick C2-deficient hypomorph mice ; ABCG5/G8 ; adenosine triphosphate&ndash ; binding cassettes G5 and G8 ; ConA ; Concanavalin A ; Npc2.Tg ; Niemann-Pick C2 transgenic mice ; PCR ; polymerase chain reaction ; qPCR ; quantitative polymerase chain reaction ; HEK ; human embryonic kidney ; BSA ; bovine serum albumin ; ALT ; alanine transaminase ; Abcb11 ; ATP-binding cassette ; sub-family B member 11 ; Abcb4 ; ATP-binding cassette ; sub-family B member 4 ; CS
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：64
• 期：2
• 页码：361-369
• 全文大小：1350 K

文摘

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.