Deficiency of Niemann-Pick C1 protein protects against diet-induced gallstone formation in mice

Morales, María Gabriela; Amigo, Ludwig; Balboa, Elisa; Acuña, Mariana; Castro, Juan Francisco; Molina, Helia; Miquel, Juan Francisco; Nervi, Flavio; Rigotti, Attilio; Zanlungo, Silvana

doi:10.1111/j.1478-3231.2010.02230.x

Cited by 9 publications

(14 citation statements)

References 51 publications

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“…While Niemann-Pick C1 (NPC1) is a key component for the intracellular distribution of cholesterol originating from lipoprotein endocytosis and plays a role in biliary cholesterol secretion ( 20 ), ABCG5/G8 directly facilitates cholesterol secretion into the bile. However, the role of ABCG5/G8 in SR-BI-mediated enhancement of biliary cholesterol secretion is currently controversial ( 19,21 ).…”

Section: Ceh Hydrolyzes Sr-bi-delivered Hdl-cementioning

confidence: 99%

Cooperation between hepatic cholesteryl ester hydrolase and scavenger receptor BI for hydrolysis of HDL-CE

Yuan

Bie

Wang

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org synthesized, results in its accumulation within the body leading to pathological consequences. Under homeostatic conditions, excess cholesterol accumulated in the peripheral tissues, e.g., arterial wall-associated macrophages, is returned back to the liver via high density lipoprotein (HDL). Liver plays a central role in the regulation of plasma cholesterol concentrations, as it is not only the major site for cholesterol synthesis and secretion of lipoproteins into blood, but it is also the sole organ able to remove cholesterol from the body. In species that do or do not express cholesteryl ester transfer protein (CETP), scavenger receptor BI (SR-BI)-mediated HDL uptake by liver represents the major mechanism for clearance of HDL-cholesterol (HDL-C) and cholesteryl esters (CEs).Hepatic SR-BI facilitates selective cholesterol uptake from HDL particles in which HDL-C as well as CEs are directly transferred to the cells without internalization and hydrolytic disassembly of the HDL particles. Free or unesterifi ed cholesterol (FC) from HDL delivered via SR-BI is thought to be directly secreted into bile without entering the hepatic metabolic pool ( 1, 2 ). Hepatic SR-BI thus regulates plasma HDL-C levels as well as the utilization of this cholesterol for biliary secretion ( 3 ). Pieters et al. ( 4 ) demonstrated that selective uptake of HDL-cholesteryl esters (HDL-CEs) is effi ciently coupled to bile acid synthesis. However, based on unchanged bile acid pool size and composition as well as fecal bile acid excretion in SR-BI Multiple pathways are involved in maintaining wholebody cholesterol homeostasis in adult organisms for which intestinal cholesterol absorption and endogenous cholesterol biosynthesis must be balanced with biliary cholesterol and bile acid secretion. Endogenous synthesis of cholesterol, which occurs predominantly in the liver, is tightly regulated by cholesterol levels. Abbreviations: AdCEH, cholesteryl ester hydrolase expressing adenovirus; AdLacZ, ␤ galactosidase expressing adenovirus; AdSR-BI, scavenger receptor BI expressing adenovirus; CE, cholesteryl ester; CEH, cholesteryl ester hydrolase; CETP, cholesteryl ester transfer protein; FC, free or unesterifi ed cholesterol; HDL-C, HDL-cholesterol; HDL-CE, HDL cholesteryl ester; MOI, multiplicity of infection; NPC1, Niemann-Pick C1; RCT, reverse cholesterol transport; SR-BI, scavenger receptor BI .

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Section: Ceh Hydrolyzes Sr-bi-delivered Hdl-cementioning

confidence: 99%

Cooperation between hepatic cholesteryl ester hydrolase and scavenger receptor BI for hydrolysis of HDL-CE

Yuan

Bie

Wang

et al. 2013

Journal of Lipid Research

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“…The abdomen was opened, the cystic duct was ligated, and a common bile duct fistula was performed with a polyethylene catheter. Hepatic bile was collected for 30 min, while mice remained hydrated, warm, and stable [22], and then blood, liver, and gallbladder were removed. The liver was immediately frozen at -80°C.…”

Section: Hepatic and Gallbladder Bile Blood And Liver Samplingmentioning

confidence: 99%

“…We have previously shown that NPC1 plays a critical role in controlling the biliary secretion of plasma lipoprotein-derived cholesterol in mice [21,22]. Hepatic NPC1 overexpression by adenovirus-mediated gene transfer increases biliary cholesterol secretion in wild-type mice and cholesterol-fed NPC1 (-/-) mice [21].…”

Section: Introductionmentioning

confidence: 98%

“…Hepatic NPC1 overexpression by adenovirus-mediated gene transfer increases biliary cholesterol secretion in wild-type mice and cholesterol-fed NPC1 (-/-) mice [21]. NPC1 (-/-) mice fed a high-cholesterol diet cannot normally process dietary cholesterol, leading to its accumulation in the liver without increasing biliary cholesterol secretion [21,22]. Furthermore, NPC1-deficient mice are highly resistant to diet-induced cholesterol gallstones due to impaired secretion of excess cholesterol into the bile [22].…”

Section: Introductionmentioning

confidence: 99%

“…NPC1 (-/-) mice fed a high-cholesterol diet cannot normally process dietary cholesterol, leading to its accumulation in the liver without increasing biliary cholesterol secretion [21,22]. Furthermore, NPC1-deficient mice are highly resistant to diet-induced cholesterol gallstones due to impaired secretion of excess cholesterol into the bile [22]. In contrast, no information is available on plasma, hepatic, and biliary lipid physiology and pathophysiology in NPC2-deficient mice fed normal chow and high-cholesterol diets.…”

Section: Introductionmentioning

confidence: 99%

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Niemann‐Pick C2 Protein Expression Regulates Lithogenic Diet‐Induced Gallstone Formation and Dietary Cholesterol Metabolism in Mice

Balboa

Morales

Aylwin

et al. 2011

Lipids

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Niemann-Pick C2 protein (NPC2) is a lysosomal soluble protein that is highly expressed in the liver; it binds to cholesterol and is involved in intracellular cholesterol trafficking, allowing the exit of lysosomal cholesterol obtained via the lipoprotein endocytic pathway. Thus, this protein may play an important role in controlling hepatic cholesterol transport and metabolism. The aim of this work was to study the relevance of NPC2 protein expression in hepatic cholesterol metabolism, biliary lipid secretion and gallstone formation by comparing NPC2 hypomorph [NPC2 (h/h)] and wild-type mice fed control, 2% cholesterol, and lithogenic diets. NPC2 (h/h) mice exhibited resistance to a diet-induced increase in plasma cholesterol levels. When consuming the chow diet, we observed increased biliary cholesterol and phospholipid secretions in NPC2 (h/h) mice. When fed the 2% cholesterol diet, NPC2 (h/h) mice exhibited low and high gallbladder bile cholesterol and phospholipid concentrations, respectively. NPC2 (h/h) mice fed with the lithogenic diet showed reduced biliary cholesterol secretion, gallbladder bile cholesterol saturation, and cholesterol crystal and gallstone formation. This work indicates that hepatic NPC2 expression is an important factor in the regulation of diet-derived cholesterol metabolism and disposal as well as in diet-induced cholesterol gallstone formation in mice.

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Intestinal and hepatic Niemann–Pick C1L1 proteins: Future therapeutic targets for cholesterol gallstones disease?

Castro-Torres¹,

O-Arciniega²,

Bravo-Duarte³

et al. 2014

European Journal of Pharmacology

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Deficiency of Niemann-Pick C1 protein protects against diet-induced gallstone formation in mice

Abstract: Hepatic NPC1 expression is an important factor for regulating the biliary secretion of diet-derived cholesterol as well as for diet-induced cholesterol gallstone formation in mice.

Cited by 9 publications

References 51 publications

Cooperation between hepatic cholesteryl ester hydrolase and scavenger receptor BI for hydrolysis of HDL-CE

Cooperation between hepatic cholesteryl ester hydrolase and scavenger receptor BI for hydrolysis of HDL-CE

Niemann‐Pick C2 Protein Expression Regulates Lithogenic Diet‐Induced Gallstone Formation and Dietary Cholesterol Metabolism in Mice

Intestinal and hepatic Niemann–Pick C1L1 proteins: Future therapeutic targets for cholesterol gallstones disease?

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